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WO2015097667A2 - A composition, process of preparation of said composition, kit and a method of treating cancer - Google Patents

A composition, process of preparation of said composition, kit and a method of treating cancer Download PDF

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Publication number
WO2015097667A2
WO2015097667A2 PCT/IB2014/067274 IB2014067274W WO2015097667A2 WO 2015097667 A2 WO2015097667 A2 WO 2015097667A2 IB 2014067274 W IB2014067274 W IB 2014067274W WO 2015097667 A2 WO2015097667 A2 WO 2015097667A2
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Prior art keywords
hydrogen
alkyl
formula
inhibitor
composition
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WO2015097667A3 (en
Inventor
Shireen VALI
Shahabuddin USMANI
Zeba SULTANA
Shweta KAPOOR
Ashish Kumar Agrawal
Taher ABBASI
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Cell Works Group Inc
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Cell Works Group Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present disclosure relates to a composition and a kit to treat cancer.
  • the disclosure provides a composition comprising AKT inhibitor and atleast one of Cyclooxygenase-2 inhibitor and 5-lipoxygenase inhibitor.
  • the disclosure further relates to a process of preparing said composition and a method of treating cancer where PDK/AKT/mTOR signaling axis is highly activated such as tumors carrying mutation of PTEN/ PBK/AKT individually or in combination with each other or in combination with mutation in other genes causing cancer.
  • Phosphatase and Tensin Homolog or PTEN is a tumor suppressor gene. It is also known as mutated in multiple advanced cancer 1 (MMAC1). It is one of the most commonly mutated of all tumour suppressor genes, and if not mutated, it is often suppressed or downregulated. Somatic PTEN mutations and deletions, and inactivation of PTEN by methylation or microRNA silencing, are common in multiple tumour types.
  • PTEN hamartoma tumour syndrome (PHTS) is a group of syndromes characterized by benign growths and a high risk for cancers of the breast, endometrium and thyroid. Cowden syndrome is the best characterized of these and 85% of patients have germline PTEN mutations.
  • Tumors associated with alteration of PTEN gene include the classical PHTS-associated tumours like breast, endometrium and thyroid, and also tumours of the central nervous system, prostate, lung, pancreas, liver and adrenal glands, as well as melanoma, leukaemia and lymphoma.
  • An analysis of PTEN gene alteration in different cancer from COSMIC website is below:
  • PTEN is a phosphatase and its lipid phosphatase activity dephosphorylates the 3- phosphoinositide products of PI3K.
  • 3-phosphoinositides can activate important survival kinases, such as phosphoinositide-dependent kinase 1 (PDK1; encoded by PDPK1 ) and AKT. Change in the phosphatase activity or deletion/downregulation of PTEN gene will result in hyper-activated AKT signalling. Hyper activation of AKT can also result due to mutations in PI3KCA and AKT genes. This hyper-activated AKT signalling will affect different processes such as cell cycle progression, metabolism, migration, apoptosis, transcription and translation. Highly activated AKT also confers resistance to different chemotherapy.
  • PTEN mutation is also associated with the resistance to different targeted therapies, for example PTEN is associated with resistance to anti-HER2 therapy and anti-EGFR therapy in Breast cancer and colorectal cancer respectively, PTEN mutated cells have also been shown to give resistance to MEK inhibitors in KRAS mutated cells, Though preclinical studies have shown that m ' TOR inhibitors as single agents have shown preclinical success in PTEN mutated profiles, in clinical trial these inhibitor have shown limited efficacy and evidences are less of PTEN mutation and mTOR inhibitor sensitivity
  • the present disclosure aims to overcome the drawbacks of the prior art by providing a composition comprising combination of compounds.
  • the present disclosure relates to a composition
  • a composition comprising: i) an AKT inhibitor, and ii) at least one of cyclooxygenase-2 inhibitor and 5 -lipoxygenase inhibitor, optionally along with a pharmaceutically acceptable excipient; a process of preparing the composition said process comprising act of: combining an AKT inhibitor and atleast one of Cyclooxygenase-2 inhibitor and 5 -lipoxygenase inhibitor optionally along with a pharmaceutically acceptable in any ratio, any concentration or any order thereof excipient to obtain the composition; a kit comprising: i) an AKT inhibitor and ii) atleast one of Cyclooxygenase-2 inhibitor and 5 -lipoxygenase inhibitor, optionally along with a pharmaceutically acceptable excipient; a method of treating cancer and associated conditions in a subject in need thereof, the method comprising administering to a subject a composition comprising: i) a therapeutically- effective amount of an AKT inhibitor, and ii)
  • Figure 1 depicts the impact of the different combinations of the instant disclosure on a Non-triggered Normal Epithelial Cell. In case of two drag combinations, each drug is taken at a concentration that causes 20% reduction in viability (IC20) calculated based on viability change in PTEN mutated profile.
  • Figure 1.1 depicts the impact of the combination CW145-CW168 on a Non-triggered Normal Epithelial Cell.
  • Figure 1.2 depicts the impact of the combination CW145-CW254 on a Non-triggi Normal Epithelial Cell.
  • Figure 1.3 depicts the impact of the combination CW145-CW168-CW254 on a Non- triggered Normal Epithelial Cell.
  • Figure 2 depicts the impact of combinations of the instant disclosure on phenotypic indexes for PTEN Mutated cell lines.
  • Cell lines and the respective profiles include U251 (PTEN and P53 mutant profile) and U87 (PTEN and P53 wild type profile).
  • the U87 cell lines are used as 'control' to assess the effect of the combinations of the instant disclosure on U251 cell line.
  • Figure 2.11 to 2.32 represent effect of combination of two or three drugs on above described cell line profiles. In case of two drag combinations, each drug is taken at a concentration that causes 20% reduction in viability (IC20) calculated based on viability change in PTEN mutated cell line. In case of three-drug combinations ( Figure 2.31 and Figure 2.32), each drug is taken at a concentration thai causes 15% reduction in viability (IC15) calculated based on viability change in PTEN mutated cell line.
  • Figure 2.11 depicts plot of the impact of Single vs. Double combination comprising of drugs CW145 and CW168 at IC20 concentration on viability phenotype in PTEN mutated cell lines.
  • Figure 2.12 depicts plot of the impact of Single vs. Double combination comprising of drags CW145 and CW168 at IC20 concentration on proliferation phenotype in PTEN mutated cell lines.
  • Figure 2.21 depicts plot of the impact of Single vs. Double combination comprising of drugs CW145 and CW254 at IC20 concentration on viability phenotype in PTEN mutated cell lines.
  • Figure 2.22 depicts plot of the impact of Single vs. Double combination comprising of drugs CW 145 and CW254 at IC20 concentration on proliferation phenotype in PTEN mutated cell lines.
  • Figure 2.31 depicts the impact of Single vs. Double vs. Triple combination comprising of drugs CW 145, CW 168 and CW254 at IC15 concentration on viability phenotype in PTEN mutated cell lines.
  • Figure 2.32 depicts the impact of Single vs. Double vs. Triple combination comprising of drags CWT45, CW168 and CW254 at IC15 concentration on proliferation phenotype in PTEN mutated cell lines.
  • FIG. 3 depicts the impact of combinations of the present disclosure on biomarkers for PTEN mutated cell lines.
  • Biomarkers such as apoptotic biomarkers Caspase 3 (CASP3) and PARP1 cleaved; cell cycle checkpoint complexes CDK2-CCNE and CD 4-CCND1 as proliferation biomarkers and biomarkers such as RHEB-GTP and RPS6 downstream of the AKT-niTOR pathway that impact the translation machinery are predictively assayed.
  • Biomarkers such as apoptotic biomarkers Caspase 3 (CASP3) and PARP1 cleaved
  • cell cycle checkpoint complexes CDK2-CCNE and CD 4-CCND1 as proliferation biomarkers
  • biomarkers such as RHEB-GTP and RPS6 downstream of the AKT-niTOR pathway that impact the translation machinery are predictively assayed.
  • Figure 3.11 depicts the impact of Single vs. Double combination comprising of drugs CW145 and CW168 at IC20 concentration on CASP3, an apoptosis biomarker, in PTEN mutated cell lines.
  • Figure 3.12 depicts the impact of Single vs. Double combination comprising of drugs CW 145 and CW168 at IC20 concentration on PARP1 Cleaved, an apoptosis biomarker, in PTEN mutated cell lines.
  • Figure 3.13 depicts the impact of Single vs. Double combination comprising of drugs CW145 and CW168 at IC20 concentration on CDK2-CCNE complex, biomarker for proliferation phenotype, in PTEN mutated cell lines.
  • Figure 3.14 depicts the impact of Single vs. Double combination comprising of drugs CW145 and CW168 at IC20 concentration on CDK4-CCND1 complex, biomarker for proliferation phenotype, in PTEN mutated cell lines.
  • Figure 3.15 depicts the impact of Single vs. Double combination comprising of drugs CW145 and CW168 at IC20 concentration on RHEB-GTP, biomarker to monitor protein translation, in PTEN mutated cell lines.
  • Figure 3.16 depicts the impact of Single vs. Double combination comprising of drags CW145 and CW168 at IC20 concentration on RPS6, biomarker to monitor protein translation, in PTEN mutated cell lines.
  • Figure 3.21 depicts the impact of Single vs. Double combination comprising of drugs CW145 and CW254 at IC20 concentration on CASP3 in PTEN mutated cell lines.
  • Figure 3.22 depicts the impact of Single vs. Double combination comprising of drugs CW145 and CW254 at IC20 concentration on PARPl Cleaved in PTEN mutated cell lines.
  • Figure 3.23 depicts the impact of Single vs. Double combination comprising of drugs CW145 and CW254 at IC20 concentration on CDK2-CCNE complex in PTEN mutated cell lines.
  • Figure 3.24 depicts the impact of Single vs. Double combination comprising of drugs CW145 and CW254 at IC20 concentration on CDK4-CCND1 complex in PTEN mutated cell lines.
  • Figure 3.25 depicts the impact of Single vs. Double combination comprising of drugs CW1.45 and CW254 at IC20 concentration on RHEB-GTP in PTEN mutated cell lines.
  • Figure 3.26 depicts the impact of Single vs. Double combination comprising of drags CW145 and CW254 at IC20 concentration on RPS6 in PTEN mutated cell lines.
  • Figure 3.31 depicts the impact of Single vs. Double vs. Triple combination comprising of drugs CW145, CW168 and CW254 at IC15 concentration on CASP3 in PTEN mutated cell lines
  • Figure 3.32 depicts the impact of Single vs. Double vs. Triple combination comprising of drugs CW145, CW168 and CW254 at IC15 concentration on PARPl Cleaved in PTEN mutated cell lines.
  • Figure 3.33 depicts the impact of Single vs. Double vs. Triple combination comprising of drags CW145, CW168 and CW254 at IC15 concentration on CDK2- CCNE complex in PTEN mutated cell lines.
  • Figure 3.34 depicts the impact of Single vs. Double vs. Triple combination comprising of drugs CW145, CW168 and CW254 at IC15 concentration on CDK4- CCND1 complex in PTEN mutated cell lines.
  • Figure 3.35 depicts the impact of Single vs. Double vs. Triple combination comprising of drags CW145, CW168 and CW254 at IC15 concentration on KHEB- GTP in PTEN mutated cell lines.
  • Figure 3.36 depicts the impact of Single vs. Double vs. Triple combination comprising of drugs CW145, CW168 and CW254 at IC15 concentration on RPS6 in PTEN mutated cel l lines.
  • Figure 4 depicts scientific rationale for the diflerent combinations of the present disclosure.
  • Figure 4.1 depicts scientific rationale for the CW145-CW168 combination.
  • Figure 4.2 depicts scientific rationale for the CW145-CW254 combination.
  • Figure 4.3 depicts scientific rationale for the CW145-CW 168-CW254 combination.
  • Figure 5 depicts the impact of variable dosages of the drug as single agent and in combination on key phenotypes - Viability and Proliferation in PTEN mutated cell lines U87 and U251.
  • the drag having variable dosage is CW145, other drugs in combination CW168, and CW254 are kept at fixed dosage equivalent to IC20 in case of two drug combination and IC15 in case of three drug combination,
  • Figure 5.11 depicts dose response of single drag CW145 with concentration C equal to IC20 and its combination with fixed doses of CW168 at IC20 concentrations having effect on viability index in PTEN mutated cell line -U87.
  • Figure 5.12 depicts dose response of single dr g CW145with concentration C equal to IC20 and its combination with fixed doses of CW168 at IC20 concentrations having effect on proliferation index in PTEN mutated cell line -TJ87.
  • Figure 5.21 depicts dose response of single drug CW145 with concentration C equal to IC20 and its combination with fixed doses of CW168 at IC20 concentrations having effect on viability index in PTEN mutated cell line -U251.
  • Figure 5,22 depicts dose response of single drug CW145with concentration C equal to 1C20 and its combination with fixed doses of CW168 at IC20 concentrations having effect on proliferation index in PTEN mutated cell line -U251.
  • Figure 5.31 depicts dose response of single drug CW145 with concentration C equal to IC20 and its combination with fixed doses of CW254 at IC20 concentrations having effect on viability index in PTEN mutated cell line -U87,
  • Figure 532 depicts dose response of single drug CW145 with concentration C equal to IC20 and its combination with fixed doses of CW254 at IC20 concentrations having effect on proliferation index in PTEN mutated cell line -U87.
  • Figure 5.41 depicts dose response of single drug CW145 with concentration C equal to IC20 and its combination with fixed doses of CW254 at IC20 concentrations having effect on viability index in PTEN mutated cell line -U251 .
  • Figure 5.42 depicts dose response of single drug CW145 with concentration C equal to IC20 and its combination with fixed doses of CW254 at IC20 concentrations having effect on proliferation index in PTEN mutated cell line -U251.
  • Figure 5.51 depicts dose response of single drug CW145 with concentration C equal to 1C15 and its combination with fixed doses of CW ' 168 and CW254 at 1C15 concentrations having effect on viability index in PTEN mutated cell line -U87.
  • Figure 5.52 depicts dose response of single drug CW145with concentration C equal to IC15 and its combination with fixed doses of CW168 and CW254 at IC15 concentrations having effect on proliferation index in PTEN mutated cell line -U87,
  • Figure 5.61 depicts dose response of single drug CW 145 with concentration C equal to IC15 and its combination with fixed doses of CW168 and CW254 at IC15 concentrations having effect on viability index in PTEN mutated cell line -U251.
  • Figure 5,62 depicts dose response of single drug CW145with concentration C equal to IC15 and its combination with fixed doses of CW ' 168 and CW254 at 1C15 concentrations having effect on proliferation index in PTEN mutated cell line -U251.
  • Figure 6-11 depicts in-vitro experiments showing the impact of variable dosages of the dnig as single agent and in combination on relative growth in PTEN mutated and PTEN wild-type cell lines. From figure 6 to 8, CW145 tested is MK2206 and from figure 9 to 11, CW145 tested is Nelfinavir,
  • Figure 6 depicts the percentage change in the relative growth of the PTEN mutated ceil line U251 at single, two and three drag combinations of CW 145. CW168 and CW254.
  • individul dosage of CW145, CW168 and CW254 are taken at 5, 50 and 100 uM respectively.
  • 1/10 th of CW145 (0.5 ⁇ ), Half of CW168 (25 ⁇ ) and Half of CW254 (50 ⁇ ) concentration is taken.
  • Figure 7 depicts the percentage change in the relative growth of the PTEN mutated cell line U251 at single, two and three drag combinations of CW 145, CW168 and CW254.
  • Fixed dosage of CW145 (0.5 ⁇ ) and CW254 (50 ⁇ ) is taken along with varying dosage of CW168 (25 and 50 ⁇ )
  • Figure 8 depicts the percentage change in the relative growth of the PTEN mutated cell line U87 and PTEN wild type cell line LN229 at single, two and three drag combinations of CW145, CW168 and CW254, On the x-axis, fixed dosage of CW145, CW168 and CW254 are taken at 0.5, 25 and 50 ⁇ respectively.
  • Figure 9 depicts the percentage change in the relative growth of the PTEN mutated cell line U251 at single, two and three dr g combinations of CW145, CW168 and CW254. On the x-axis, fixed dosage of CW145, CW168 and CW254 are taken at 20, 20 and 50 ⁇ respectively.
  • Figure 10 depicts the percentage change in the relative growth of the PTE mutated cell line U87 at single, two and three drug combinations of CW 145, CW168 and CW254.
  • fixed dosage of CW145, CW168 and CW254 are taken at 20, 20 and 50 ⁇ respectively.
  • Figure 11 depicts the percentage change in the relative growth of the PTEN mutated cell line U251 and PTEN wild type cell line LN229 at single, two and three drug combinations of CW145, CW168 and CW254.
  • fixed dosage of CW145, CW168 and CW254 are taken at 15, 20 and 50 ⁇ respectively.
  • the present disclosure provides multi -targeted combination therapeutic approach to suppress and cure symptoms associated with Cancers and associated conditions.
  • the dnig combinations were validated using Virtual Tumor Cell Platform and cell line experiments as described herein.
  • the present disclosure provides two, and three drag combinations, which provide multi-targeted combination therapeutic approach to suppress and cure symptoms associated with PTEN/PDKCA/AKT mutant Cancers and associated conditions, wherein the Cancer is associated with mutation in PTEN/PDKCA/AKT alone or in combination with each other or in combination with other genes causing cancer.
  • the drag combinations were validated using cell line experiments in human glioma cell lines- U251MG and U87 as described herein.
  • the present disclosure focuses on PTEN/PD /AKT mutant tumors irrespective of tissue subtype or origin, with PTEN-PDK-AKT pathway being the predominant driver in the cancer cell.
  • the main focus of the present disclosure is to study the biochemical dynamics of cancers carrying mutations in PTEN/PDK/AKT and design therapies that are effective in this aggressive untreatable subset of cancers.
  • the two and three -drag combinations provide synergistic efficacy on the end-point markers, while dosing is as low as 1 /4, 1/3 or 1/2 of the recommended therapeutic dose of the drag in humans.
  • Using a lower dose of the individual drag also provides an advantage in terms of minimizing the intensity of side-effects or toxicities associated with the drags.
  • the drug combination works by inhibiting multiple targets minimally, so that an amplified effect is observed on all of the primary end-point markers and at the same time ensuring that all the targets have primary response ability, so as to negate the possibility of immune suppression and secondary infections.
  • use of smaller doses of individual drugs also lower the cost of manufacture and formulation, providing an improved effect at lower price to the subject.
  • Smaller doses also mitigate wasteful administration of a drag to a physiological system that has been saturated or has reached a peak therapeutic response from smaller, synergistic doses.
  • the important advantages provided by the compounds, compositions, methods and uses of the present disclosure are:
  • the compounds used in the the composition of the instant disclosure is alternatively referred as "pharmaceutical composition", “compound(s)", “drug(s)”, “inhibitors” throughout the specification.
  • pharmaceutical composition pharmaceutical composition
  • compound(s) drug(s)
  • drug(s) drug(s)
  • inhibitors inhibitors
  • reference to combination of 2 drug(s)/compound(s) are alternatively made as “2 drag Combination”, “2D”
  • reference to combination of 3 drug(s)/compound(s) are alternatively made as “3 drag Combination”, “3D” throughout the specification
  • mutation includes deletion, insertion, amplification of a gene etc.
  • the present disclosure relates to a composition
  • a composition comprising: i) an AKT inhibitor; and ii) at least one of cyclooxygenase-2 inhibitor and 5-lipoxygenase inhibitor; optionally along with a pharmaceutically acceptable excipient.
  • the present disclosure also relates to a process of preparing a composition comprising: i, an AKT inhibitor; and ii, atleast one of Cyclooxygenase-2 inhibitor and 5-lipoxygenase inhibitor; optionally along with a pharmaceutically acceptable excipient, said process comprising act of: combining an AKT inhibitor and atleast one of Cyclooxygenase-2 inhibitor and 5-lipoxygenase inhibitor optionally along with a pharmaceutically acceptable excipient, in any ratio, any concentration or any order thereof.
  • kits comprising: i. an AKT inhibitor; and ii. atleast one of Cyclooxygenase-2 inhibitor and 5-lipoxygenase inhibitor; optionally along with a pharmaceutically acceptable excipient.
  • the present disclosure also relates to a method of treating cancer and associated conditions in a subject in need thereof, the method comprising administering to a subject a composition comprising: i) a therapeutically-effective amount of an AKT inhibitor; and
  • the present disclosure also relates to use of a composition comprising: i) an AKT inhibitor; and ii) atleast one of Cyclooxygenase-2 inhibitor and 5-lipoxygenase inhibitor; optionally along with a pharmaceutically acceptable excipient in the preparation of a medicament for the treatment of cancer and associated conditions.
  • the AKT inhibitor is a direct or indirect inhibitor.
  • the AKT inhibitor is a direct inhibitor when it binds to AKT thereby causing inhibition whereas an indirect inhibitor causes inhibition of AKT through the inhibition of other proteins, These proteins may be involved in AKT pathway or may be any protein whose inhibition leads to inhibition of AKT,
  • AKT inhibitor is an indirect inhibitor which inhibits AKT and also inhibits other proteins involved in the same disease condition or a different disease condition.
  • the composition comprises an AKT inhibitor and cyclooxygenase-2 inhibitor optionally along with a pharmaceutically acceptable excipient.
  • the composition comprises an AKT inhibitor and 5-lipoxygenase inhibitor optionally along with a pharmaceutically acceptable excipient.
  • the composition comprises an AKT inhibitor, cyclooxygenase-2 inhibitor and 5-lipoxygenase inhibitor optionally along with a pharmaceutically acceptable excipient.
  • the AKT inhibitor is selected from a group comprising compound of:
  • R is halogen, Rl and R2 are alkyl or hydrogen
  • R3, R4, R5, R6 are hydrogen or alkyl
  • R7, R8, R9, RIO, Rl 1 , R12 are alkyl or hydrogen
  • R13, R14 are alkyl or hydrogen, R15 is halo
  • R16, R17, R18 are alkyl or hydrogen, R19 is halogen
  • R20 is halogen
  • R21 , R22, R23 are alkyl or hydrogen
  • R24, R25, R26, R27, R29 are alkyl or hydrogen, R28 is halogen Formula 1(h):
  • R30, R31 ,R33, R35, R36 are alkyl or hydrogen; R32, R34 are alkyl
  • R37, R38, R39 are alkyl or hydrogen Formula l(j):
  • R40, R41 , R42 are alkyl or hydrogen
  • R43, R44 are alkyl or hydrogen Formula 1(1):
  • R45, R46, R47, R48, R49, R50 are alkyl or hydrogen
  • R51, R52, R53, R54,R56 are alkyl or hydrogen; R55 is halogen Formula l(n):
  • Zl, Z2, 73, Z4, Z5,Z6,Z7, Z8, Z9, Z10 are alkyl or hydrogen Formula l(p):
  • Zl l, Z12, Z13, Z14, Z15, Z16 are alkyl or hydrogen Formula l(q):
  • Z17, Z19, Z20, Z21 are alkyl or hydrogen;
  • Z18 is halogen Formula l(r):
  • Z22, Z23, Z24, Z25, Z26, Z27 and Z28 are alkyi or hydrogen Formula l(s):
  • Z29, Z30, Z31 , Z32, Z33, Z34, Z35, Z36, Z37, Z38, Z39 are alkyi or hydrogen
  • Z48, Z49, Z50, Z51, Z52, Z53, Z54 are alkyl or hydrogen
  • Z55, Z56, Z57, Z58, Z59, Z60, Z61 are hydrogen or alkyl Formula l(w):
  • Z62, Z63, Z64, Z65, Z66, Z67, Z68 are hydrogen or alkyl Formula l(x):
  • Z78, Z79, Z80, Z81 , Z82, Z83 are alkyl or hydrogen; a pharmaceutically-acceptable salt of any of the foregoing and combination thereof.
  • the AKT inhibitor selected from a group comprising compounds of formula l(o), l(p), l(q), l(r), l(s), l(t), l(u), l(v), l (w), ] (x) and l(y) is also an HIV protease inhibitor.
  • the Cyclooxygenase-2 inhibitor is selected from a group comprising compounds of:
  • XI , X2 and X3 are hydrogen or alkyl; X is halogen
  • X4 and X5 are hydrogen or alkyl
  • X8 is halogen
  • X9, X10, Xl l are alkvl or hydrogen
  • X17, X18, X19, X20 are alkyl or hydrogen
  • X28 is halogen
  • X29, X30, X31 are alkyl or hydrogen
  • X32, X33, X34 are alkyl or hydrogen
  • X35, X36, X37 are alkyl or hydrogen
  • X38 is halogen
  • X39,X40, X41 are alkyl or hydrogen
  • X42, X43 are hydrogen or alkyl
  • X48, X49 are alkyl or hydrogen;
  • X50 is halogen Formula 2(r):
  • X51 is cycloalkyi or aryl
  • X52, X53 are alkyl or hydrogen
  • erein X54, X55, X56 are alkyl or hydro
  • X57, X58, X59, X60, X61 are alkyl or hydrogen
  • X62 is alkyl or hydrogen
  • X66, X67, X68, X69 are alkyl or hydrogen and X70 is halogen
  • X73, X74, X75 are hydrogen or alkyl and X76 is halogen
  • X80, X81, X82 are alkyl or hydrogen; X83 is halogen;
  • the 5-lipoxygenase inhibitor is selected from a group comprising compounds of:
  • Y2, Y3, Y4, Y5, Y7, Y 8 are alkyl or hydrogen; Y6 is halogen
  • Y15 is hydrogen or alkyl
  • Y16, Y17, Y 18, Y19 are alkyl or hydrogen
  • Y22, Y23,Y24, Y25 are aikyi or hydrogen; a pharmaceutically-acceptable salt of any of the foregoing and combination thereof,
  • the pharmaceutically-acceptable excipient is a granulating agent, binding agent, lubricating agent, disintegrating agent, sweetening agent, glidant, anti-adherent, anti-static agent, surfactant, anti -oxidant, gum, coating agent, coloring agent, flavouring agent, coating agent, plasticizer, preservative, suspending agent, emulsifying agent, plant cellulosic material, spheronization agent, immediate release agent, controlled release agent, sustained delayed release agent or combination thereof.
  • the composition is in a dosage form selected from a group comprising feed, food, pellet, lozenge, liquid, elixir, aerosol, inhalant, spray, powder, tablet, pill, capsule, gel, geltab, nanosuspension, nanoparticle, microgel, suppository troches, aqueous or oily suspensions, ointment, patch, lotion, dentifrice, emulsion, cream, drop, dispersible powder or granule, emulsion in hard or soft gel capsule, syrup, phytoceutical, nutraceutical and combination thereof.
  • the composition is a dosage form having an immediate release, a controlled release or a sustained delayed release mechanism.
  • the composition is a dosage form formulated for mode of administration selected from a group comprising intravenous, subcutaneous, intramuscular, oral, rectal, aerosol, parenteral, ophthalmic, pulmonary, transdermal, vaginal, otic, nasal, topical administration and combination thereof.
  • the cancer and associated conditions are caused by mutation in PTE /PBK/AKT alone or in combination with each other or in combination with mutation in other genes causing cancer.
  • the cancer is selected from a group comprising glioblastoma multiforme, endometrial cancer, ovarian cancer, prostate cancer, breast cancer, lung cancer, colorectal cancer, pancreatic cancer, brain cancer, head and neck cancer, glioblastoma, multiple myeloma, acute non lymphocytic leukemia and myelodysplasia, or any combination of conditions thereof.
  • the therapeutically effective amount of the AKT inhibitor is from about 10% to about 100% of a maximum tolerated dose; the therapeutically effective amount of the cyclooxygenase-2 inhibitor is from about 10% to about 100% of a maximum tolerated dose; and the therapeutically effective amount of the 5-lipoxygenase inhibitor is from about 10% to about 100%) of a maximum tolerated dose.
  • the therapeutically effective amount of the AKT inhibitor is from about I mg to about 3000 mg; the therapeutically effective amount of the cyclooxygenase-2 inhibitor is from about 1 mg to about 3000 mg; and the therapeutically effective amount of the 5-lipoxygenase inhibitor is from about 1 mg to about 3000 mg.
  • the present disclosure also relates to a method of inhibiting cancer cells/inducing cytotoxicity in cancer cells/ modulating markers in cancer cells, said method comprising act of contacting the cancer cells with a composition comprising: i. an AKT inhibitor; and ii. atleast one of Cyclooxygenase-2 inhibitor and 5 -lipoxygenase inhibitor; optionally along with a pharmaceutically acceptable excipient.
  • the method of inhibiting cancer cells/ inducing cytotoxicity in cancer ceils/ modulating markers in cancer cells include methods of reducing/inhibiting proliferation of cancer cells, methods of reducing/inhibiting viability of cancer cells nducing apoptosis of cancer cells etc.
  • modulating the markers in cancer cells include increasing/decreasing the levels of certain markers in cancer cells.
  • the AKT inhibitors belong to a class of anti-cancer agents or HIV protease inhibitors or a combination thereof
  • Cyclooxygenase-2 inhibitors belong to a class of non-steroidal anti-inflammatory agents (NSAID)
  • 5-lipoxygenase inhibitors belong to a class of anti-asthmatic agents.
  • said cancer/condition is any cancer with PTEN/PI3K/AKT mutation individually or in combination with each other or in combination with mutation in other genes.
  • the said cancer is any cancer including, but not limiting to, cancers of the central nervous system such as glioblastoma multiforme, endometrial cancer, ovarian cancer, prostate cancer, breast cancer, pancreatic cancer, colorectal cancer, lung cancer, head and neck cancer, multiple myeloma, acute non lymphocytic leukemia or myelodysplasia, or any combination of conditions thereof, or any condition having a mutation therein.
  • said mutation is a PTEN gene mutation or PI3K. gene mutation or AKT gene mutation in combination with other gene mutations that support cancer, selected but not restricted to a group comprising EGFR, RAS, B-catenin, CDKN2A, P13KCA, APC, MYC, BCL2, SOCS1, TP53and SMAD4 or any combination thereof.
  • the present disclosure provides a composition comprising a combination of AKT inhibitor and atleast one of Cyclooxygenase-2 inhibitor and a 5- lipoxygenase inhibitoralong with pharmaceutically acceptable excipients.
  • the present disclosure provides a kit comprising a composition of AKT inhibitor and atleast one of Cyclooxygenase-2 inhibitor and a 5 -lipoxygenase inhibitor along with pharmaceutically acceptable excipients, wherein the kit comprises one or a plurality of dosage forms, AKT inhibiting compounds- CW145:
  • CW145class of drug is an inhibitor of AKT or specific inhibitor of HIV protease that also inhibits AKT
  • HIV protease inhibitors are orally available drugs developed to specifically inhibit the HIV aspartyl protease, a retroviral enzyme that cleaves the viral gag-pol polyprotein necessary for the production of infectious viral particles and that lacks mammalian close homologs. These drags are approved for anti-viral therapy for HIV infected patients. However, it was determined that these drugs can cause insulin resistance that was determined to be due to inhibition of AKT signaling. Clinical studies demonstrated that HIV positive patients receiving these drags had an inhibition of their phosphorylated AKT levels. Thus, these drags were tested in tumor cells and found to demonstrate anti-neoplastic effect, primarily through their inhibition of AKT.
  • AKT inhibition a few of the drags from this class of compounds have been shown to moderately inhibit the proteasomal activity and cause ER stress but only at very high concentrations of the compound.
  • AKT inhibition and anti-neoplastic activity is achieved at the CMax concentrations obtained with the approved dose range.
  • AKT is highly activated in PTEN mutated or PTEN null profiles or PI3KCA mutant or AKT mutant profiles.
  • PTEN is a tumor suppressor gene which carries out the dephosphorylation of PIP3 to PIP2, leading to inactivation of AKT/mTOR signaling pathway.
  • PTEN mutation or PTEN loss results in accumulation of PIP3 which in turn activates AKT and PDK1.
  • PDK1 carries out further phosphorylation and activation of AKT.
  • AKT can be highly activated with PI3KCA mutation or AKT mutation.
  • the constitutively activated AKT drives cell survival, proliferation and cellular metabolism through its downstream signaling such as inhibitory phosphorylation of downstream pro-apoptotic proteins like FO.XO, GSK3B etc, activation of mTORCl which phosphorylates p70 ribosomal protein S6 kinase (S6K) and eukaryotic translation-initiation factor 4E (eIF4E)-binding protein 1 (4EBP1) to activate protein translation and cell proliferation.
  • mTORCl further activates HIF1 which is a key transcription factor for many cellular metabolism genes and also plays an important role in angiogenesis.
  • CW145 causes growth inhibition of PTEN mutated or PTEN null or PI3KCA mutant or AKT mutant profiles having constitutively activated AKT.
  • AKT inhibition the negative feedback loop from mTOR on AKT via IRS1 becomes weak thereby reducing the overall inhibition on AKT and hence increased concentration of the drug is needed to abrogate complete AKT signaling.
  • Such high concentration of the drug may be toxic for the normal and healthy cells also.
  • CW168 class of drug is an inhibitor of COX-2 which is reported to have high expression levels in PTEN profiles via the AKT - NF-kB ⁇ COX2 transcription. Inhibition of COX-2 will also result in reduced levels of prostaglandins like PGE2, PGI2 and PGD2, thereby reducing the GPCR mediated activation of ⁇ by these prostaglandins farther augmenting the effect of CW 145. ⁇ activity has been reported to be high in PTEN profiles and hence the above inhibition will make the combination more specific to profiles harboring PTEN mutation or loss. CW168 will also help in reducing the pro-angiogenic effect of prostaglandins.
  • any compound CW145 and any compound CW168 in any amount, ratio, concentration, or order thereof inhibit upregulated AKT signaling and COX-2 signaling in PTEN null/mutated profiles.
  • the combination is specific for PTEN null/mutated profiles or PI3K/AKT mutated/amplified profiles where the expression of COX-2 is mainly driven by ⁇ / ⁇ pathway and not ERK/p38. Also, in such profiles the RAS/RAF/ERK pathway axis is not dominant.
  • CW145 can activate ERK, p38 and JNK by relieving inhibitory effect of AKT on these kinases. Activated ERK, p38 and JNK will increase API and NF-kB signaling which in turn may upregulate COX-2 expression. This high COX-2 expression will lead to increase in GPCR signaling. High GPCR will increase cAMP level which in turn will activate PKA, PKA is known to inhibit RAF signaling and thus will compensate AKT negative feedback on RAF.
  • CW145 alone in PTEN wild-type profiles may show significant effect by upregulation of COX2/GPCR/PKA pathway which will keep in check the over-activation of ERK pathway.
  • presence of CW168 in combination of CW145 will release this dual inhibition of AKT and PKA on RAF resulting in high ERK signaling. This may have a negative therapeutic impact as the pathway driving tumorigenesis in such profiles would be increasing. Thus, these profiles will show resistance to this combination.
  • CW254 class of drug is an ALOX5 inhibitor.
  • ALOX5 expression is reported to be high in PTEN mutant/null profiles, via AKT ⁇ > NFKB ⁇ > ALOX5 transcription. Inhibition of ALOX5 will also result in reduced levels of leukotrienes like LTB4, LTC4, LTD4 and LTE4 thereby, reducing the GPCR mediated activation of ⁇ 3 ⁇ by these leukotrienes further augmenting the effect of CW145.
  • ⁇ 3 ⁇ activity has been reported to be high in PTEN profiles and hence the above inhibition will make the combination of CW145 and CW254 more specific to profiles harboring PTEN mutation or loss.
  • any compound CW145 and any compound CW254 in any amount, ratio, concentration, or order thereof inhibit upregulated AKT signaling and ALOX5 signaling in PTEN null/mutated profiles.
  • the combination affect highly upregulated PI3K/AKT pathway by attacking it from two sides. One is the direct inhibition of AKT and another is inhibition of I' 13 K B signaling via down regulation of GPCR. This strategic combination reduces the actual concentration of single agents without compromising efficacy on PI3K/AKT pathway. Lower dosage also reduces the unwanted toxicities.
  • the combination also reduces angiogenesis process by inhibiting leukotriene pathway,
  • compositions of the present disclosure provide a surprising advantage over the individual compounds.
  • the present disclosure relates to combination of any compound CW145and atleast one of any compound CW168 and any compound CW254 in any amount, ratio, concentration, or order thereof which synergistically inhibits the PI3 /AKT signaling pathway, the GPCR mediated activation of ⁇ 3 ⁇ and PDKy and in turn causes downstream activation of AKT and activate the AMPK mediated inhibition of mTOR pathway.
  • the CW145 class of drugs are anti-cancer agents and they function as AKT inhibitor and/or HIV protease inihibitors.
  • the CW168 class of drugs are non- steroidal anti -inflammatory drugs (NSAID) and they function as Cyclooxygenase-2 inhibitor.
  • NSAID non- steroidal anti -inflammatory drugs
  • the CW254 class of drugs are antiasthmatic drags and they function as 5 -lipoxygenase inhibitor.
  • CW145168 refers to a combination of any CW145 compound, and any CW 168 compound in any amount, ratio, concentration, or order thereof.
  • CW145254 refers to a combination of any CW145 compound, and any CW254 compound in any amount, ratio, concentration, or order thereof.
  • CW145168254 refers to a combination of any CW145 compound, any CW168 compound and any CW254 compound in any amount, ratio, concentration, or order thereof.
  • Non-limiting examples of CW145 include:
  • Non-limiting examples of CW 168 include:
  • n Indomethacin or indorneiacin or Meiindol or Imbrilon or Indocid or Indocin or Tannex or Amuno or Indomethacine or Indomethacinum or 2-[l-(4- chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetic acid.
  • o Ketoprofen or Profenid or Orudis or Alrheumat or Alrheurnun or Capisien or Oruvail or Actron or Epatec or 2-(3-benzoylphenyl)propanoic acid.
  • Niflurii or Landruma Nifistive Acid or Niflurii or Landruma or Forenol or Actol or Donalgin Niflumate or Niflam or Nifluminic acid or 2- (trifluoromethyl)anilino]pyridine-3-carboxylic acid.
  • Non-limiting examples of CW254 include:
  • Non-limiting examples of CW145 include the compounds of Table 1A.
  • Non-limiting examples of CW168 include the compounds of Table 2.
  • Non-limiting examples of CW254 include the compounds of Table 3.
  • the disclosure provides the use of pharmaceutically-acceptable salts of any compound described herein.
  • Pharmaceutically-acceptable salts include, for example, acid-addition salts and base-addition salts.
  • the acid that is added to the compound to form an acid-addition salt can be an organic acid or an inorganic acid.
  • a base that is added to the compound to form a base-addition salt can be an organic base or an inorganic base.
  • a pharmaceutically-acceptable salt is a metal salt.
  • a pharmaceutically-acceptable salt is an ammonium salt.
  • Metal salts arise from the addition of an inorganic base to a compound of the disclosure,
  • the inorganic base consists of a metal cation paired with a basic counterion, such as, for example, hydroxide, carbonate, bicarbonate, or phosphate.
  • the metal can be an alkali metal, alkaline earth metal, transition metal, or main group metal.
  • the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium or zinc.
  • a metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt or a zinc salt.
  • Ammonium salts can arise from the addition of ammonia or an organic amine to a compound of the disclosure.
  • the organic amine is triethyl amine, diisopropyl amine, ethanol amine, diethanol amine, Methanol amine, morpholine, N-methylmorpholine, piperidine, N- methylpiperidine, N-ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrrazole, pipyrrazole, imidazole, pyrazine, or pipyrazine.
  • an ammonium salt is a triethyl amine salt, a diisopropyl amine salt, an ethanol amine salt, a diethanol amine salt, a Methanol amine salt, a morpholine salt, an -methylmo holine salt, a piperidine salt, an N- methylpiperidine salt, an N-ethylpiperidine salt, a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrrazole salt, a pipyrrazole salt, an imidazole salt, a pyrazine salt, or a pipyrazine salt.
  • Acid addition salts can arise from the addition of an acid to a compound of the disclosure.
  • the acid is organic.
  • the acid is inorganic.
  • the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, a phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisinic acid, gluconic acid, glucaronic acid, saccaric acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, citric acid, oxalic acid or maleic acid.
  • the salt is a hydrochloride salt, a hydrobromi.de salt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfate salt, a sulfite salt, a phosphate salt, isonicotinate salt, a lactate salt, a salicylate salt, a tartrate salt, an ascorbate salt, a gentisinate salt, a gluconate salt, a glucaronate salt, a saccarate salt, a formate salt, a benzoate salt, a glutamate salt, a pantothenate salt, an acetate salt, a propionate salt, a butyrate salt, a fumarate salt, a succinate salt, a methanesulfonate (mesylate) salt, an etlianesulfonate salt, a benzenesulfonate salt, a p- to
  • excipients are selected from a group comprising granulating agents, binding agents, lubricating agents, disintegrating agents, sweetening agents, glidants, anti-adherents, anti-static agents, surfactants, antioxidants, gums, coating agents, coloring agents, flavouring agents, coating agents, plasticizers, preservatives, suspending agents, emulsifying agents, plant cellulosic material, spheroni.zati.on agents and any combination thereof.
  • the present disclosure further relates to a process for obtaining a composition of CW145and atleast one of the compounds selected from a group comprising CW.168 and CW254, optionally along with pharmaceutically acceptable excipient(s), said process comprising act of combining said compounds in any order thereof.
  • the pharmaceutical composition of the disclosure is a combination of any pharmaceutical compounds described herein with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • the pharmaceutical composition facilitates administration of the compound to an organism.
  • Pharmaceutical compositions are administered in therapeutically-effective amounts as pharmaceutical compositions by any form and route known in the art including, for example, intravenous, subcutaneous, intramuscular, oral, rectal, aerosol, parenteral, ophthalmic, pulmonary, transdermal, vaginal, otic, nasal, and topical administration.
  • the pharmaceutical composition is administered in a local or systemic manner, for example, through injection of the compound directly into an organ, optionally in a depot or sustained release formulation.
  • Pharmaceutical compositions are provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.
  • a rapid release form provides an immediate release.
  • An extended release formulation provides a controlled release or a sustained delayed release.
  • pharmaceutical compositions for oral administration is formulated readily by combining the active compounds with pharmaceutically acceptable carriers or excipients well known in the art. Such carriers can be used to formulate tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like, for oral ingestion by a subject.
  • pharmaceutical preparations for oral use is obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Cores can be provided with suitable coatings.
  • concentrated sugar solutions can be used, which may optionally contain an excipient such as gum arable, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments are added to the tablets or dragee coatings, for example, for identification or to characterize different combinations of active compound doses.
  • pharmaceutical preparations which are used orally include push-fit capsules made of gelatin, as well as soil, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the capsule comprises a hard gelatin capsule comprising one or more of pharmaceutical, bovine, and plant gelatins.
  • a gelatin may be alkaline processed.
  • the push-fit capsules contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds are dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols, Stabilizers may be added. All formulations for oral administration are provided in dosages suitable for such administration.
  • compositions are tablets, lozenges, or gels, forbuccal or sublingual administration.
  • parental injections are formulated for bolus injection or continuous infusion.
  • the pharmaceutical compositions are in a form suitable for parenteral injection as a sterile suspension, solution or emulsion in oily or aqueous vehicles, and contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Suspensions of the active compounds can be prepared as oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen- free water, before use.
  • the active compounds are administered topically and are formulated into a variety of topically administrate compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, and ointments,
  • Such pharmaceutical compositions may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • formulations suitable for transdermal administration of the active compounds may employ transdermal delivery devices and transdermal delivery patches, and may be lipophilic emulsions or buffered aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive.
  • patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical compounds.
  • Transdermal delivery may be accomplished by means of iontophoretic patches and the like. Additionally, transdermal patches provide controlled delivery. The rate of absorption is slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel . Conversely, absorption enhancers may be used to increase absorption.
  • transdermal devices can be in the form of a bandage comprising a backing member, a reservoir containing compounds and carriers, a rate controlling barrier to deliver the compounds to the skin of the subject at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • the active compounds for administration by inhalation are in a form as an aerosol, a mist, or a powder.
  • Pharmaceutical compositions are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, diehlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant for example, dichlorodifluoromethane, trichlorofluoromethane, diehlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit is determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator is formulated containing a powder mix of the compounds and a suitable powder base such as lactose or starch.
  • the compounds are fonnulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like.
  • a low-melting wax such as a mixture of fatty acid glycerides, optionally in combination with cocoa butter, is first melted.
  • therapeutically- effective amounts of the compounds described herein are administered in pharmaceutical compositions to a subject having a disease or condition to be treated.
  • the subject is a mammal such as a human
  • a therapeutically- effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compounds used and other factors.
  • the compounds are used singly or in combination with one or more therapeutic agents as components of mixtures.
  • compositions are formulated using one or more physiologically-acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations that can be used pharmaceutically. Formulation is modified depending upon the route of administration chosen.
  • Pharmaceutical compositions comprising compounds described herein are manufactured in a conventional manner, for example, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
  • the pharmaceutical compositions include at least one pharmaceutically acceptable carrier, diluent, or excipient and compounds described herein as free-base or pharmaceutically-acceptable salt form.
  • the methods and pharmaceutical compositions described herein include the use of crystalline forms (also known as polymorphs), and active metabolites of these compounds having the same type of activity.
  • compositions comprising the compounds described herein include formulating the compounds with one or more inert, pharmaceutically-acceptable excipients or carriers to form a solid, semi-solid, or liquid composition.
  • Solid compositions include, for example, powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • Liquid compositions include, for example, solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein.
  • Semi-solid compositions include, for example, gels, suspensions and creams.
  • compositions can be in liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions may also contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives.
  • composition comprising compounds can be delivered via liposomal technology.
  • liposomes as drug earners increases the therapeutic index of the compounds. Liposomes are composed of natural phospholipids, and contain mixed lipid chains with surfactant properties (e.g., egg phosphatidyl eihanolamine).
  • a liposome design employs surface ligands for attaching to unhealthy tissue.
  • Non-limiting examples of liposomes include the multilamellar vesicle (MLV), the small unilamellarvesicle (SUV), and the large unilamellar vesicle (LUV).
  • LUV multilamellar vesicle
  • SUV small unilamellarvesicle
  • LUV large unilamellar vesicle
  • Liposomal physicochemical properties are modulated to optimize penetration through biological barriers and retention at the site of administration, and to prevent premature degradation and toxicity to non-target tissues.
  • Optimal liposomal properties depend on the administration route: large-sized liposomes show good retention upon local injection, small-sized liposomes are better suited to achieve passive targeting.
  • ADCs antibody-drug conjugates
  • drugs are conjugated/fused to tumor-specific antibodies so as to deliver the drug to the site of tumor and increase their therapeutic efficacy.
  • ADCs have been developed for targeted delivery of anticancer drugs to tumor in the patient body with the aim of bypassing the morbidity common to conventional drug delivery.
  • non-limiting examples of dosage forms suitable for use in the disclosure include feed, food, pellet, lozenge, liquid, elixir, aerosol, inhalant, spray, powder, tablet, pill, capsule, gel, geltab, nanosuspension, nanoparticle, microgel, suppository troches, aqueous or oily suspensions, ointment, patch, lotion, dentifrice, emulsion, creams, drops, dispersible powders or granules, emulsion in hard or soft gel capsules, syrups, phytoceuticals, nutraceuticals and any combination thereof.
  • non-limiting examples of pharmaceutically-acceptable excipients suitable for use in the disclosure include granulating agents, binding agents, lubricating agents, disintegrating agents, sweetening agents, glidants, anti-adherents, anti-static agents, surfactants, anti- oxidants, gums, coating agents, coloring agents, flavouring agents, coating agents, plasticizers, preservatives, suspending agents, emulsifying agents, plant cellulosic material and spheronization agents, and any combination thereof.
  • a composition of the disclosure is, for example, an immediate release form or a controlled release formulation.
  • An immediate release formulation is formulated to allow the compounds to act rapidly.
  • Non-limiting examples of immediate release formulations include readily dissolvable formulations.
  • a controlled release formulation is a pharmaceutical formulation that has been adapted such that drug release rates and drag release profiles can be matched to physiological and chronotherapeutic requirements or, alternatively, has been formulated to effect release of a drug at a programmed rate.
  • Non-limiting examples of controlled release formulations include granules, delayed release granules, hydrogels (e.g., of synthetic or natural origin), other gelling agents (e.g., gel-forming dietary fibers), matrix -based formulations (e.g., formulations comprising a polymeric material having at least one active ingredient dispersed through), granules within a matrix, polymeric mixtures, granular masses, and the like.
  • compositions of the disclosure are delivered through a time-controlled delivery system.
  • a suitable time-controlled delivery system is the PULSINCAP® system, or a variant thereof.
  • the time-controlled delivery system may further comprise pH-dependent systems, microbially-triggered delivery systems, or a combination thereof.
  • the time-controlled system may comprise a water insoluble capsule body enclosing a drug reservoir.
  • the capsule body may be closed at one end with a hydrogel plug.
  • the hydrogel plug can comprise swellable polymers, erodible compressed polymers, congealed melted polymers, enzymatically-controUed erodible polymers, or a combination thereof,
  • the swellable polymers include polymethacrylates.
  • Non-limiting examples of erodible compressed polymers include hydroxypropyl methylcellulose, polyvinyl alcohol, polyvinyl acetate, polyethylene oxide, and combinations thereof.
  • Non-limiting examples of congealed melted polymers include saturated polyglycolated glycerides, glycerylmonooleate, and combinations thereof.
  • Non-limiting examples of enzymatically-controUed erodible polymers include polysaccharides; amylose; guar gum; pectin; chitosan; inulin; cyclodextrin; chondroitin sulphate; dextrans; locust bean gum; arabinogalactan; chondroitin sulfate; xylan; calcium pectinate; pectin/chitosan mixtures; amidated pectin; and combinations thereof.
  • the time-controlled delivery system comprise a capsule, which farther comprises an organic acid.
  • the organic acid may be filled into the body of a hard gelatine capsule.
  • the capsule may be coated with multiple layers of polymers.
  • the capsule may be coated first with an acid soluble polymer, such as EUDRAGIT' 8 ' E, then with a hydrophilic polymer, such as hydroxypropyl methylcellulose, and finally with an enteric coating, such as EUDRAGIT ® L.
  • an additional example of a suitable time-controlled delivery system is the CHRONOTROPIC* system, or a variant thereof, which comprises a drag core that is coated with hydroxypropyl methylcellulose and an outer enteric film.
  • an additional example of a suitable time- controlled delivery system is the CODES iM system, or a variant thereof.
  • the time- controlled delivery system comprise a capsule body, which can house, for example, a drug-containing tablet, an erodible tablet, a swelling expulsion excipient, or any combination thereof.
  • the capsule may comprise an ethyl cellulose coat.
  • the time- controlled delivery system may comprise two different sized capsules, one inside the other.
  • the space between the capsules may comprise a hydrophilic polymer.
  • the drug-containing core can be housed within the inner capsule.
  • the drug delivery system comprise an impermeable shell, a drag-containing core, and erodibie outer layers at each open end, When the outer layers erode, the drug is released.
  • examples of suitable multiparticulate drag delivery systems include DIFFUCAPS ® , DIFFUTAB ® , ORB EX A ® , Eli RA ! MINITABS ® , MICROCAPS ® and variants thereof.
  • the drug delivery system comprise multiparticulate beads, which are comprised of multiple layers of the drug compound, excipients, and release-controlling polymers.
  • the multiparticulate beads comprise an organic acid or alkaline buffer.
  • the multiparticulate beads comprise a solid solution of the drug compound and crystallization inhibitor.
  • the drug delivery system comprise a matrix tablet containing water-soluble particles and the drug compound.
  • the matrix tablet may further comprise hydrophiiic and hydrophobic polymers.
  • particles in the micron size range are used.
  • nanoparticle colloidal carriers composed of natural or synthetic polymers are used.
  • a controlled release formulation is a delayed release form.
  • a delayed release form is formulated to delay a compound's action for an extended period of time.
  • a delayed release form is formulated to delay the release of an effective dose of one or more compounds, for example, for about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, or about 24 hours.
  • a controlled release formulation is a sustained release form.
  • a sustained release form is formulated to sustain, for example, the compound's action over an extended period of time.
  • a sustained release form is formulated to provide an effective dose of any compound described herein (e.g., provide a physiologically-effective blood profile) over about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21 , about 22, about 23, or about 24 hours.
  • a tablet providing a sustained or controlled release comprise a first layer containing one or two of the compounds described herein, and a tablet core containing one or two other compounds.
  • the core can have a delayed or sustained dissolution rate.
  • Other exemplary embodiments include a barrier between the first layer and core, to limit drag release from the surface of the core. Barriers can prevent dissolution of the core when the pharmaceutical formulation is first exposed to gastric fluid.
  • a barrier comprise a disintegrant, a dissolution-retarding coating (e.g., a polymeric material, for example, an enteric polymer such as a Eudragit polymer), or a hydrophobic coating or film, and may be selectively soluble in either the stomach or intestinal fluids.
  • a dissolution-retarding coating e.g., a polymeric material, for example, an enteric polymer such as a Eudragit polymer
  • a hydrophobic coating or film may be selectively soluble in either the stomach or intestinal fluids.
  • the barriers can cover substantially the whole surface of the core.
  • non-limiting examples of pharmaceutically-acceptable excipients can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995): Hoover, John E., Remington 's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkinsl999), each of which is incorporated by reference in its entirety.
  • compositions described herein are in unit dosage forms suitable for single administration of precise dosages.
  • the formulation is divided into unit doses containing appropriate quantities of one or more compounds.
  • the unit dosage is in the form of a package containing discrete quantities of the formulation.
  • Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules.
  • Aqueous suspension compositions are packaged in single-dose non-reclosable containers. Multiple-dose reclosable containers may be used, for example, in combination with a preservative.
  • Formulations for parenteral injection are presented in unit dosage form, for example, in ampoules, or in multi-dose containers with a preservative.
  • the compound described herein is present in a composition at a range of about 1 mg to about 3000 mg; from about 5 mg to about 1000 mg, from about 10 mg to about 500 mg, from about 50 mg to about 250 mg, from about 100 mg to about 200 mg, from about 1 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 150 mg, from about 150 mg to about 200 mg, from about 200 mg to about 250 mg, from about 250 mg to about 300 mg, from about 300 mg to about 350 mg, from about 350 mg to about 400 mg, from about 400 mg to about 450 mg, from about 450 mg to about 500 mg, from about 500 mg to about 550 mg, from about 550 mg to about 600 mg, from about 600 mg to about 650 mg, from about 650 mg to about 700 mg, from about 700 mg to about 750 mg, from about 750 mg to about 800 mg, from about 800 mg to about 850 mg, from about 850 mg to about 900 mg, from about 900 mg to about 950 mg, or from about 500 mg to about 550
  • the compound described herein is present in a composition in an amount of about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, or about 2000 mg.
  • a dose is expressed in terms of an amount of the drug divided by the mass of the subject, for example, milligrams of drag per kilograms of subject body mass.
  • the composition comprises from about 625mg/day to about 3000mg/day of CW145, from about 600mg/kg/day to about 2400mg/kg/day of CW254and from about 200mg/day to about 800mg/day of CW168.
  • CW145 is present in a composition in an amount ranging from about 250 mg/kg to about 2000 mg/kg, about 10 mg/kg to about 800 mg/kg, about 50 mg/kg to about 400 mg/kg, about 100 mg kg to about 300 mg/kg, or about 150 mg/kg to about 200 mg kg.
  • CW254or CW168 is present in a composition in an amount ranging from about 1 mg/kg to about 300 mg/kg, about 2 mg/kg to about 200 mg/kg, about 3 mg kg to about 100 mg/kg, about 5 mg/kg to about 75 mg/kg, about 10 mg/kg to about 50 mg kg or about 20 mg/kg to about 40 mg kg
  • the composition comprises from about 100 mg/day to about 800 mg/day of CW145, from about 20 mg/kg/day to about 25 mg/kg/day of CW254or from about 5mg/day to about 80mg/day of CW168.
  • CW145 is present in a composition in an amount ranging from about 600mg/kg to about 3000 mg/kg, about 10 mg/kg to about 800 mg/kg, about 50 mg kg to about 400 mg/kg, about 100 mg/kg to about 300 mg/kg, or about 150 mg/kg to about 200 mg/kg.
  • CW254 (include range from 600 to 2400 mg/day) or CW168 (range from 200 - 800 mg/day) is present in a composition in an amount ranging from about 1 mg/kg to about 300 mg/kg, about 2 mg/kg to about 200 mg/kg, about 3 mg kg to about 100 mg/kg, about 5 mg/kg to about 75 mg/kg, about 10 mg/kg to about 50 mg kg or about 20 mg/kg to about 40 mg/ ' kg.
  • the composition comprises from about 600 mg/day to about 3000mg/day of CW 145, from about 600 mg/kg/day to 2400 mg/kg/day of CW254 or from about lOOmg/day to about 800mg/day of CW168.
  • the compound described herein is present in a composition in an amount that is a fraction or percentage of the maximum tolerated amount.
  • the maximum tolerated amount is as determ ined in a subject, such as a mouse or human.
  • the fraction is expressed as a ratio of the amount present in the composition divided by the maximum tolerated dose.
  • the ratio is from about 1/20 to about 1/1.
  • the ratio is about 1/20, about 1/19, about 1/18, about 1/17, about 1/16, about 1/15, about 1/14, about 1/13, about 1/12, about 1/11, about 1/10, about 1/9, about 1/8, about 1/7, about 1/6, about 1/5, about 1/4, about 1/3, about 1/2, or about 1/1.
  • the ratio is 1/20, 1/19, 1/18, 1/17, 1/16, 1/15, 1 /14, 1/13, 1/12, 1/1 1 , 1/10, 1/9, 1/8, 1/7, 1/6, 1/5, 1/4, 1/3, 1/2, or 1/1.
  • the ratio is in a range from about 5% to about 100%, from about 10% to about 100%, from about 5% to about 80%, from about 10% to about 80%, from about 5% to about 60%, from about 10% to about 60%, from about 5% to about 50%, from about 10% to about 50%, from about 5% to about 40%, from about 10% to about 40%, from about 5% to about 20%, or from about 10% to about 20%.
  • the ratio is about 5%, about 10%, about 15%: ⁇ , about 20%>, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%).
  • Dosages are altered depending on a number of variables, including, for example, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
  • dose is modulated to achieve a desired pharmacokinetic or pharmacodynamics profile, such as a desired or effective blood profile, as described herein.
  • pharmacokinetic and pharmacodynamic data is obtained by techniques known in the art.
  • Appropriate pharmacokinetic and pharmacodynamic profile components describing a particular composition may vary due to the inherent variation in pharmacokinetic and pharmacodynamic parameters of drug metabolism in human subjects.
  • Pharmacokinetic and pharmacodynamic profiles are based on the determination of the mean parameters of a group of subjects.
  • the group of subjects includes any reasonable number of subjects suitable for determining a representative mean, for example, 5 subjects, 1 0 subjects, 1 6 subjects, 20 subjects, 25 subjects, 30 subjects, 35 subjects, or more.
  • the mean is determined by calculating the average of all subject's measurements for each parameter measured.
  • the pharmacokinet c parameters are any parameters suitable for describing a compound disclosed herein.
  • the Cmax may be not less than about 100 ng/mL; not less than about 200 ng/mL; not less than about 300 ng/mL; not less than about 400 ng/mL; not less than about 500 ng/mL; not less than about 600 ng/mL; not less than about 700 ng/mL; not less than about 800 ng/mL; not less than about 900 ng/mL; not less than about 1000 ng/mL; not less than about 1 250 ng/mL; not less than about 1 500 ng/mL; not less than about 1750 ng/mL; not less than about 2000 ng/mL; or any other C max appropriate for describing a pharmacokinetic profile of a compound described herein.
  • the T ma of a compound present in a composition described herein may be, for example, not greater than about 0.5 hours, not greater than about 1.0 hours, not greater than about 1.5 hours, not greater than about 2.0 hours, not greater than about 2.5 hours, not greater than about 3.0 hours, or any other T inax appropriate for describing a pharmacokinetic profile of a compound described herein.
  • the AU o-mf ) of a compound present in a composition described herein may be, for example, not less than about 250 ng » hr/mL, not less than about 500 ng'hr/mL, not less than about 1000 ng » hr/mL, not less than about 1500 ng » hr/mL, not less than about 2000 ng » hr/mL, not less than about 3000 ng'hr/mL, not less than about 3500 ng ir/mL, not less than about 4000 ng » hr/mL, not less than about 5000 ng » hr/mL, not less than about 6000 ng » hr/mL, not less than about 7000 ng e hr/mL, not less than about 8000 ng'hr/mL, not less than about 9000 ng » nr/mL, or any other AUC ( o..i r .
  • the plasma concentration of a compound present in the composition described herein about one hour after administration is, for example, not less than about 25 ng/niL, not less than about 50 ng/mL, not less than about 75 ng/mL, not less than about 100 ng/mL, not less than about 150 ng/mL, not less than about 200 ng/mL, not less than about 300 ng/mL, not less than about 400 ng/mL, not less than about 500 ng/mL, not less than about 600 ng/mL, not less than about 700 ng/mL, not less than about 800 ng/mL, not less than about 900 ng/mL, not less than about 1000 ng/mL, not less than about 1200 ng/mL, or any other plasma concentration of a compound described herein.
  • the pharmacodynamic parameters are parameters suitable for describing compositions of the disclosure.
  • the pharmacodynamic profile may exhibit decreases in viability phenotype for the tumor cells or tumor size reduction in tumor cell lines or xenograft studies, for example, about 24 hours, about 48 hours, about 72 hours, or 1 week.
  • the present disclosure further relates to a method for treating a subject either suspected of having or having condition or mutation or a combination thereof wherein said condition is selected from a group comprising, but not limiting to, cancers of the central nervous system such as glioblastoma multiforme, endometrial cancer, ovarian cancer, prostate cancer, breast cancer, pancreatic cancer, colorectal cancer, lung cancer, brain Cancer, head and neck cancer, multiple myeloma, acute non lymphocytic leukemia and myelodysplasia, or any combination of conditions thereof, or any condition having a mutation therein,
  • cancers of the central nervous system such as glioblastoma multiforme, endometrial cancer, ovarian cancer, prostate cancer, breast cancer, pancreatic cancer, colorectal cancer, lung cancer, brain Cancer, head and neck cancer, multiple myeloma, acute non lymphocytic leukemia and myelodysplasia, or any combination of conditions thereof, or any condition having a
  • the cancers wherein said mutation is in PTEN/PI3K/AKT genes alone or in combination with each other or in combination with mutation in other genes that promote cancer similar but not limited to BRAF, KRAS, EGFR, B-catenin, CD N2A, , APC, MYC, BCL2, SOCS1, SMAD4, TP53 etc or any combination of mutations thereof, said method comprising act of administering to the subject- composition of CW145 and atleast one of compound selected from a group comprising CW168 and CW254, or any combination thereof, optionally along with pharmaceutically acceptable excipient(s);
  • the compounds are administered as composition of C WHS and atleast one of compound selected from group comprising of CW168 and CW254, or any combination thereof, optionally along with pharmaceutically acceptable excipient(s); at time interval ranging from about 1 second to about 64800seconds; or
  • each of the compounds is in ratio ranging from about IC 10 dose to IC 80 .
  • oncology disease system of the present disclosure is a very comprehensive representation of the bio-molecular activity involved in the solid and liquid tumors.
  • the system includes all the pathways and bio- molecular interactions in the key phenotypes of Cancer, such as viability, apoptosis, proliferation, angiogenesis and metastasis.
  • the Virtual Tumor Cell Platform of the present disclosure consists of a dynamic and kinetic representation of the signaling pathways underlying tumor physiology at the bio-molecular level with coverage on all the key tumor phenotypes including proliferation, viability, angiogenesis, metastasis, apoptosis, tumor metabolism and tumor microenvironment related to associated inflammation.
  • the technology is a comprehensive coverage of protein players; associated gene and mRNA species with regard to tumor related signaling.
  • the platform subset coverage includes signaling pathways comprising growth factors like EGFR, PDGFRA, FGFR, c- ET, VEGFR.
  • IGF-I R cell cycle regulators, mTOR signaling, p53 signalingcascade, cytokine pathways like ILL IL4, IL6, IL12, IL15 TNF; TGF-b, hypoxia mediated regulation, angiogenic promoters, lipid mediators and tumor metabolism and others. It has a wide coverage of kinases and transcription factors associated with tumor physiology network.
  • the modeling of the time- dependent changes in the fluxes of the constituent pathways is done utilizing modified ordinary differential equations (ODE) and mass action kinetics.
  • ODE modified ordinary differential equations
  • the current version of the technology includes over 6500biological species with over thirty thousand cross- talk interactions.
  • the platform is prospectively and retrospectively validated against an extensive set of pre-defined in vitro and in vivo studies.
  • the starting control state of the system is based on normal epithelial cell physiology that is non-tumorigenic.
  • the user can control the transition of the normal system to a neoplastic disease state aligning with specific tumor mutation profiles. This is accomplished as an example through over- expression of the tumori genie genes like EGFR, IGF-IR; knock-downs of the tumor- suppressors like p53, PTEN; and increased states of hypoxia and oxidative stress. Knockdowns or over-expressions of biological species can be done at the expression or activity levels.
  • drags are represented in this technology through explicit mechanism of action specification and the drug concentration in the virtual experiments is explicitly assumed to be post ADME (Absorption, Distribution, Metabolism, and Excretion).
  • ADME Absorption, Distribution, Metabolism, and Excretion
  • multiple virtual patient profiles are generated by overlaying the functional impact of mutations. Therapeutics that is being designed is tested against this panel of virtual patients to understand the differential sensitivity of the therapy to the multiple patient profiles. This system of testing is the first step on the road to designing and tailoring therapies for individual patients.
  • composition and the process of preparing the composition for the purpose of improving one or more undesirable symptoms associated with the disease states or for slowing the progression (worsening) of one or more symptoms associated with the disease is provided.
  • therapeutic combinations comprising at least one member of a first group and at least one member of a second group; wherein members of the first group are selected from the group consisting of an AKT inhibitor and; and members of the second group are selected from the group consisting of a Cyclooxygenase-2 inhibitor and 5 -lipoxygenase inhibitor.
  • the therapeutic combination can comprise: at least one AKT inhibitor (CW145) and at least one Cyclooxygenase-2 inhibitor (CW168) and/or at least one 5 -lipoxygenase inhibitor (CW254).
  • MK-2206 is an orally active allosteric Akt inhibitor that is under development for the treatment of solid tumors. MK-2206 is a highly potent and selective Akt inhibitor. It is equally potent toward purified recombinant human Aktl (IC50, 5 nmol/L) and Akt2 enzyme (IC50, 12 nmol/L) and approximately 5-fold less potent against human Akt3 (IC50, 65 nmol/L;)
  • Akt inhibitor MK2206 binds to and inhibits the activity of Akt in a non-ATP competitive manner. MK-2206 inhibits phosphorylation at both Thr308 and Ser473 residues of AKT
  • Absorption Slow absolution, with median time to maximum measured plasma concentration values ranging from 4 to 10 hours.
  • Nelfinavir is an anti-viral compound that specifically inhibits the HIV aspartyl protease, a retroviral enzyme that cleaves the viral gag-pol polyprotein required for the production of infectious viral particles. This also has anti-neoplastic activity mediated through inhibition of AKT phosphorylation. At higher concentrations, Nelfinavir can inhibit the beta 2 (trypsin-like activity) subunit along with the beta 1 and beta 5 (chymotrypsin like activity) of the proteasome and induce endoplasmic reticulum stress. It is used in combination with other antiviral drugs in the treatment of H IV in both adults and children.
  • Indication Used in combination with other antiviral drugs in the treatment of HIV in both adults and children.
  • HIV protease inhibitors such as Nelfmavir have been reported to cause AKT inhibition at 20 uM which is in the range of concentration of the drug achievable in plasma at therapeutically approved dosage. [PMID 23454896]. Inhibition of AKT phosphorylation at Ser473 has been reported to be an independent mechanism of drug action in this study as opposed to other papers that report AKT inhibition as a consequence of proteasome inhibition and consequent unfolded protein response. [PMID : 17460771]. However, direct/indirect inhibition of AKT by HIV protease inhibitors is well reported and has been seen in patients taking the medication.
  • HIV protease inhibitor AKT inhibitor
  • Proteasome inhibitor Absorption: Well absorbed following oral administration.
  • CYP450 cytochrome P450
  • CYP3A and CYP2C19 appear to be the predominant enzymes that metabolize nelfmavir in humans.
  • One major and several minor metabolites are found in plasma; the major oxidative metabolite has in vitro antiviral activity comparable to that of the parent drag.
  • the terminal half-life in plasma was typically 3.5 to 5 hours.
  • Nelfmavir is an FD A approved drug.
  • present disclosure also envisages the use of:
  • Dosage Form - Capsule, Route - Oral, Strength - 50 nig, 100 mg, 200 mg, 400 mg
  • Celecoxib is a non-steroidal anti-inflammatory drag (NSAID) used in the treatment of osteoarthritis, rheumatoid arthritis, acute pain, painful menstruation and menstrual symptoms, and to reduce numbers of colon and rectum polyps in patients with familial adenomatous polyposis.
  • NSAID non-steroidal anti-inflammatory drag
  • OA osteoarthritis
  • RA rheumatoid arthritis
  • JRA juvenile rheumatoid arthritis
  • ankylosing spondylitis acute pain
  • primary dysmenorrhea oral adjunct to usual care for patients with familial adenomatous polyposis
  • Celecoxib a selective cyclooxygenase-2 (COX-2) inhibitor, is classified as a nonsteroidal anti-inflammatory drug (NSAID).
  • NSAID nonsteroidal anti-inflammatory drug
  • Celecoxib is used to treat rheumatoid arthritis, osteoarthritis, and familial adenomatous polyposis (FAP). Because of its lack of platelet effects, celecoxib is not a substitute for aspirin for cardiovascular prophylaxis. It is not known if there are any effects of celecoxib on platelets that may contribute to the increased risk of serious cardiovascular thrombotic adverse events associated with the use of celecoxib.
  • PGE2 Inhibition of PGE2 synthesis may lead to sodium and water retention through increased fluid reabsorption in the renal medullary thick ascending loop of Henle and perhaps other segments of the distal nephron. In the collecting ducts, PGE2 appears to inhibit water reabsorption by counteracting the action of antidiuretic hormone.
  • celecoxib The mechanism of action of celecoxib is believed to be due to inhibition of prostaglandin synthesis. Unlike most NSAIDs, which inhibit both types of cyclooxygenases (COX-1 and COX-2), Celecoxib is a selective non-competitive inhibitor of cycl.ooxygenase-2 (COX-2) enzyme, it binds with its polar sulfonamide side chain to a hydrophilic side pocket region close to the active COX-2 binding site. Both COX-1 and COX-2 catalyze the conversion of arachidonic acid to prostaglandin (PG) H2, the precursor of PGs and thromboxane.
  • COX-1 and COX-2 catalyze the conversion of arachidonic acid to prostaglandin (PG) H2
  • PG prostaglandin
  • Absorption Well absorbed in the gastrointestinal tract. When a single dose of 200 mg is given to healthy subjects, peak plasma levels occur 3 hours after an oral dose. The peak plasma level is 705 ng/mL.Absolute bioavailability studies have not been conducted. When multiple doses are given, steady-state is reached on or before Day 5. When taken with a high fat meal, peak plasma levels are delayed for about 1 to 2 hours with an increase in total absorption (AUG) of 10% to 20%.
  • AUG total absorption
  • Half Life The effective half-life is approximately 11 hours when a single 200 mg dose is given to healthy subjects. Terminal half-life is generally variable because of the low solubility of the drug thus prolonging absorption.
  • Celecoxib is eliminated predominantly by hepatic metabolism with little ( ⁇ 3%) unchanged drug recovered in the urine and feces, 57% of the oral dose is excreted in the feces and 27% is excreted into the urine, The primary metabolite in urine and feces was the carboxylic acid metabolite (73%)). The amount of glucuronide in the urine is low.
  • Class of Drugs involved in this category Acemetacin, Acetaminophen, Aspirin, Diclofenac, DuP-697, Etodolac, FK-3311, Flufenamic Acid, Flurbiprofen, FR- 122047, ibuprofen, Indomethacin, Ketoprofen, Ketorolac, Naproxen, Niflumic Acid, Nimesulide, NS-398, Piroxicam, Resveratrol, Rofecoxib, SC-560, SC-58125, Sulmdac, Talniflumate, Tenidap, Valdecoxib
  • Celecoxib is an FDA approved drug.
  • the recommended dosage of ZYFLO CR for the treatment of patients with asthma is two 600 mg extended-release tablets twice daily, within one hour after morning and evening meals, for a total daily dose of 2400 mg.
  • Leukotrienes are substances that induce numerous biological effects including augmentation of neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, increased capillary permeability, and smooth muscle contraction. These effects contribute to inflammation, edema, mucus secretion, and bronchoconstriction in the airways of asthmatic patients. Zileuton relieves such symptoms through its selective inhibition of 5 -lipoxygenase, the enzyme that catalyzes the formation of leukotrienes from arachidonic acid. Specifically, it inhibits leiikotriene LTB4, LTC4, 1.1 1)4. and LTE4 formation. Both the R(+) and S(-) enantiomers are pharmacologically active as 5 -lipoxygenase inhibitors in in-vitro systems. Brand Name: Leutrol, Zyilo, Zyilo CR
  • Zileuton is an asthma drug that differs chemically and pharmacologically from other antiasthmatic agents. It blocks leukotriene synthesis by inhibiting 5 -lipoxygenase, an enzyme of the eicosanoid synthesis pathway. Current data indicates that asthma is a chronic inflammatory disorder of the airways involving the production and activity of several endogenous inflammatory mediators, including leukotrienes.
  • Sulfide-peptide leukotrienes (LTC4, LTD4, LTE4, also known as the slow-releasing substances of anaphylaxis) and LTB4, a chemoattractant for neutrophils and eosinophils, are derived from the initial unstable product of arachidonic acid metabolism, leukotriene A4 (LTA4), and can be measured in a number of biological fluids including bronchoalveolar lavage fluid (BALF) from asthmatic patients.
  • BALF bronchoalveolar lavage fluid
  • Leukotrienes are substances that induce numerous biological effects including augmentation of neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, increased capillary permeability, and smooth muscle contraction. These effects contribute to inflammation, edema, mucus secretion, and bronchoconstriction in the airways of asthmatic patients. Zileuton relieves such symptoms through its selective inhibition of 5 -lipoxygenase, the enzyme that catalyzes the formation of leukotrienes from arachidonic acid. Specifically, it inhibits leukotriene LTB4, LTC4, LTD4, and LTE4 formation.
  • Both the R(+) and S(-) enantiomers are pharmacologically active as 5 -lipoxygenase inhibitors in in- vitro systems. Due to the role of leukotrienes in the pathogenesis of asthma, modulation of leukotriene formation by interruption of 5 -lipoxygenase activity may reduce airway symptoms, decrease bronchial smooth muscle tone, and improve asthma control.
  • Metabolism Hepatic. Zileuton and its N-dehydroxylated metabolite are oxidatively metabolized by the cytochrome P450 isoenzymes 1 A2, 2C9 and 3A4.
  • Half Life 2.5 hours
  • Elimination of zileuton is predominantly through metabolism with a mean terminal half-life of 2.5 hours.
  • the urinary excretion of the inactive N- dehydroxylated metabolite and unchanged zileuton each accounted for less than 0.5% of the dose.
  • Zileuton is an FDA approved drug.
  • the present disclosure provides a process for preparing a composition, the composition comprising one or more compounds, wherein the compounds are CW145, CW168 and CW254, wherein the composition optionally comprises a pharmaceutically-acceptable excipient, wherein the process comprises the step of combining the compounds and the optional excipient in any order thereof.
  • the disclosure described herein provides therapeutic methods for the treatment of cancer and associated conditions, or combinations thereof.
  • the disclosure provides a method for treating a subject either suspected of having or having a condition or mutation or a combination thereof!, wherein said condition is selected from a group comprising cancers with PTEN/PI3K/AKT mutations including lung cancer, colorectal cancer, pancreatic cancer, glioblastoma, multiple myeloma etc or any combination of conditions thereof, or wherein said mutation co-occurs with each other or with other cancer promoting mutations such as those in genes similar but not limited to EGFR, KRAS, NRAS, B-catenin, CD N2A, P13K.CA, APC, MYC, BCL2, SOCS1, SMAD4, TP53 or any combination of mutations thereof, said method comprising act of administering to the subject a combination of - a) therapeutically-effective amount of an AKT inhibitor and atleast one of b) therapeutically-
  • the disclosure provides a use of a composition in the preparation of a medicament for the treatment of cancer and associated conditions, the composition comprising: an AKT inhibitor and at least one of a Cyclooxygenase-2 inhibitor anda 5 -lipoxygenase inhibitor.
  • compositions containing compounds described herein are administered for prophylactic and/or therapeutic treatments.
  • the compositions are administered to a subject already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition, or to cure, heal, improve, or ameliorate the condition itself.
  • Amounts effective for this use can vary based on the severity and course of the disease or condition, previous therapy, the subject's health status, weight, and response to the drugs, and the judgment of the treating physician. Pharmaceuticaliy-acceptabie amounts are determined by routine experimentation, for example, by a dose escalation clinical trial.
  • multiple therapeutic agents are administered in any order or simultaneously. If simultaneously, the multiple therapeutic agents are provided in a single, unified form, or in multiple forms, for example, as multiple separate pills. The compounds are packed together or separately, in a single package or in a plurality of packages. One or all of the therapeutic agents are given in multiple doses. If not simultaneous, the timing between the multiple doses may vary to as much as about a month. In anembodiment, composition of the disclosure is administered sequentially at a time interval. The time interval ranges from about 1 second to about 800minut.es.
  • compositions of the disclosure are packaged as a kit.
  • a kit includes written instructions on the use of the composition. The instructions can provide information on the identity of the therapeutic agent(s), modes of administration, or the indications for which the therapeutic agent(s) are used.
  • therapeutics are combined with genetic or genomic testing to determine whether that individual is a carrier of a mutant gene that is known to be correlated with certain diseases or conditions.
  • a personalized medicine approach may be used to provide companion diagnostic tests to discover a subject's predisposition to certain conditions and susceptibi lity to therapy.
  • a subject who is an anti- EGFR non responder may be identified through companion diagnostics.
  • the companion diagnostic test can be performed on a tumor biopsy.
  • Instructions on the use of a companion diagnostic test are provided on written material packaged with a compound, composition, or kit of the disclosure.
  • the written material may be, for example, a label.
  • the written material may suggest conditions or genetic features relevant to inflammation or the therapeutic compounds of the disclosure.
  • the instructions provide the subject and the supervising physician with the best guidance for achieving the optimal clinical outcome from the administration of the therapy.
  • compounds/composition described herein are administered before, during, or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound may vary.
  • the compounds are used as a prophylactic and are administered continuously to subjects with a propensity to conditions or diseases in order to prevent the occurrence of the disease or condition.
  • the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms.
  • the administration of the compounds may be initiated within the first 48 hours of the onset of the symptoms, within the first 24 hours of the onset of the symptoms, within the first 6 hours of the onset of the symptoms, or within 3 hours of the onset of the symptoms.
  • the initial administration may be through any route practical, such as by any route described herein using any formulation described herein,
  • a compound may be administered as soon as is practicable after the onset of a disease or a condition is detected or suspected, and for a length of time necessary for the treatment of the disease, such as, for example, from about 1 month to about .3 months.
  • the length of treatment may vary for each subject, and the length can be determined using the known criteria.
  • CW145 is MK2206 or Neifmavir (AKT inhibitor); CW168 is Ceiecoxib (COX inhibitor); CW254 is Zileuton (LOX inhibitor).
  • CW 145 is MK2206 and in examples 5 - 7, CW145 is Nelfinavir.
  • EXAMPLE 1 Virtual Tumor Based In-vivo aligned studies of Therapies of " the Disclosure
  • compositions of the disclosure were analyzed on a virtual tumor cell system designed to represent the disease state, and customized to match a specific molecular profile of specific cancer baselines. These experiments are validated by the experiment provided below.
  • the baselines selected for the virtual experiments include:
  • the system was first triggered with the respective oncogenic mutations aligned to the specific profiles and then simulated for a minimum of about 35 hours simulation time.
  • the simulation time was selected to allow the system to attain the severe oncogenic state through activation of autocrine and paracrine pathway loops affecting all oncogenic mediators like growth factors, kinases and transcription factors.
  • a system customized to the above mentioned tumor profi le is created.
  • the drug compounds CW145 CW254 and CW168 individually or in combinations were administered concomitantly to the Virtual Tumor cell, and the system simulated again for a minimum of about 18-20 hours simulation time.
  • the drag administration was performed at multiple dosage ratios across an array of samples for each drug.
  • the effect of the multiple dosage ratios was evaluated after about 1 8-20 hours of simulation time by assaying the extent of decrease/increase in the tumor cell survival, apoptosis and proliferation markers.
  • the major markers assayed include active complexes of CDK4-CCND1, CDK2-CCNE, CDK2-CCNA and CDK1-CCNB1 responsible for cell proliferation.
  • viability is a scale to measure change in tumorogenic symptoms. A reduction greater than 25% is considered as being moderately effective and a reduction greater than 40% is considered being an effective therapy.
  • Viability index is a ratio of cumulative measure of an average of survival over apoptotic markers. It is defined as a ratio of the cumulative survival index over the apoptosis index.
  • the survival index comprises of AKT1, BCL2, BIRC5, BIRC2, MCLl and XIAP, end point markers.
  • the apoptosis index comprises of BAX, CASP3, PMAIP1, CASP8, and BCL2L11.
  • Proliferation index is a cumulative measure of an average of cell cycle checkpoint complexes comprising of CD 4-CCND1 , CDK2-CCNE, CDK2-CCNA and CDK1 -
  • the combinations of compounds described herein provide therapeutic benefits at low dosage, including synergistic benefits.
  • Figure 1 illustrates the impact of different combination of drugs (CW145-CW168, CW145-CW254, CW145-CW168-CW254) on a Non-triggered normal epithelial cell
  • Figure 2 illustrates the impact of combination of drags on PTEN Mutated and PTEN wild-type cell lines.
  • the impact including phenotypic indexes (viability index and proliferation index) for the cell lines U251 (PTEN and P53 profile and U87 (PTEN profile).
  • the concentration of drug is at IC 20 for two drugs and three drugs, IC 2 o is the concentration of dnig that causes 20% reduction in viability in PTEN mutated profile.
  • Figure illustrates scientific rationales for the different combination therapies and its impact on the key phenotypes of PTEN driven cancer.
  • Figure Sillustrates the enhancement of efficacy by combining variable doses of drug CW145 with a fixed dose of drug CW168 and drag CW254 in combination on key phenotype - Viability, Proliferation in PTEN mutated cell lines
  • Example 6 U87 human glioma cell line. Drugs were tested alone Figure 10 and in combination at 20 ⁇ CW145, 20 ⁇ CW168
  • Example 7 U251 human glioma cell line and LN229 human glioma Figure 11 cell line. Drags were tested alone and in combination at
  • U251 MG human glioma cell line is procured from Sigma-Aldrich (Catalog number: 09063001). The cells are resuspended in a media containing 10% FBS (Gibco lot# 1259720) and 4X Gentamicin followed by transferring about 100 ⁇ to each well in an assay plate (3,100 cells/well; passage# 6).
  • DMSO, Digi toxin and drugs are serial diluted in an assay media. 100 ⁇ /well of the diluted sample is added to assay plate containing resuspended cells.
  • Final assay volume of each well is about 200 ⁇ , containing 10% FBS, 2X Gentamicin, DMSO, Digitoxin and drags.
  • the assay plate is incubated for about 71 hours ibllowed by addi tion of about 20 ⁇ of Promega Substrate Cei lTiter 96 Aqueous One Solution Reagent to each well. It is incubated at 37°C, The absorbance of the sample is read at about 490 nm.
  • Figure 6 illustrates concentrations of drags individually, 2 dimensional and 3 dimensional combinations on the x-axis and percentage change in relative growth on the y-axis.
  • the individual concentrations of the drags used is 5 ⁇ for CW145, 50 ⁇ for CW168 and 100 ⁇ for CW254 and at these concentrations, the individual drugs do not show much efficacy.
  • the drugs were combined in 2 dimensional combination at lowered doses of l/10 th of CW145 at 0.5 ⁇ ; half of CW168 at 25 ⁇ and half of CW 254 at 50 ⁇ .
  • the two dimensional combination at lowered doses shows a slightly better efficacy when compared to the individual drugs alone and when combined as a 3 dimensional combination of CW145 at 0.5 ⁇ , CW168 at 25 ⁇ and CW254 at 50 ⁇ , a synergistic -60% reduction in relative growth is noted that is not seen at higher concentrations of the drugs individually.
  • the example indicates that the drugs are used at lower doses when used in combination in comparison to the doses when used individually.
  • U251 MG human glioma cell line is procured from Si.gma-Aldri.ch (Catalog number: 09063001). The cells are resuspended in a media containing 10% FBS (Gibco lot# 1259720) and 4X Gentamicin followed by transferring about 100 ⁇ to each well in an assay plate (3,100 cells/well; passage# 6). DMSO, Digitoxin and drags (CW145, CW168 and CW254 individually and in combinations) are serial diluted in an assay media, 100 ⁇ /well of the diluted sample is added to assay plate containing resuspended cells.
  • Final assay volume of eac well is about 200 ⁇ , containing 10% FBS, 2X Gentamicin, DMSO, Digitoxin and drugs.
  • the assay plate is incubated for about 7 hours followed by addition of about 20 ⁇ ⁇ of Promega Substrate CellTiter 96 Aqueous One Solution Reagent to each well. It is incubated at 37°C. The absorbance of the sample is read at about 490 nm.
  • Figure 7 illustrates different dose combinations of CW145:CW168:CW254 that shows synergistic efficacy when combined together.
  • CW145 at 0.5 ⁇ when combined with CW168 at 25 ⁇ and CW254 at 50 ⁇ reduces relative growth synergistically by 60% when compared to minimal reduction in relative growth with the individual drags and when combined as a 2 dimensional combination.
  • CW168 is increased to 50 ⁇ keeping the other drug concentrations the same as before, there is an almost 99%) reduction in relative growth making this 3D combination very efficacious and synergistic.
  • the U87 human glioma cell line is procured from ATCC (American Type Culture Collection, Manassas, VA, ⁇ ; ⁇ -14TM).
  • PTEN WT LN229 cell line is procured from ATCC (American Type Culture Collection, Manassas, VA, ATCC® CRL-2611 ' ").
  • the cells are resuspended in a media containing 10% FBS (Gibco lot# 1259720) and 4X Gentamicin followed by transferring about 100 ⁇ to each well in an assay plate (3,000 cells/well; passage# 10).
  • DMSO, Digitoxin and drags are serial diluted in an assay media.
  • ⁇ /well of the diluted sample is added to assay plate containing resuspended cells.
  • Final assay volume of each well is about 200 ⁇ , containing 10% FBS, 2X Gentamicin, DMSO, Digitoxin and drugs.
  • the assay plate is incubated for about 71 hours followed by addition of about 20 ⁇ of Promega Substrate CeilTiter 96 Aqueous One Solution Reagent to each well. It is incubated at 37°C and absorbance of the sample is read at about 490 nm.
  • Figure 8 illustrates the comparison of the effect of the combination in PTEN Null U87 Cells and PTEN WT LN229 cells when combined at the same concentration of CW145 at 0.5uM, CW168 at 25uM and CW254 at 50 uM.
  • the reduction with the 2 dimensional and 3 dimensional combination is much higher in PTEN Null U87 cells when compared to PTEN WT LN229 cells.
  • With the combination of the 3 drugs there is a synergistic relative growth reduction of -60% in PTEN Null U87 cells while the relative growth reduction in the PTEN WT LN229 cells is only about 35%.
  • U251MG human glioma cell line is procured from Sigma- Aldrich (Catalog number: 09063001 ). The cells are resuspended in a media containing 10% FBS (Gibco lot# 1259720) and 4X Gentamicin followed by transferring about 100 ul to each well in an assay plate (3,100 cells/well; passage# 6). DMSO, Digitoxin and dnigs (CW145, CW168 and CW254 individually and in combinations) are serial diluted in an assay media. 100 ⁇ /well of the diluted sample is added to assay plate containing resuspended cells.
  • Final assay volume of each well is about 200 ⁇ , containing 10% FBS, 2X Gentamicin, DMSO, Digitoxin and drugs.
  • the assay plaste is incubated for about 71 hours followed by addition of about 20 ⁇ of Promega Substrate CeilTiter 96 Aqueous One Solution Reagent to each well. It is incubated at 37°C. The absorbance of the sample is read at about 490 nm.
  • Figure 9 illustrates that when the cells are incubated with the each of the drugs alone at the indicated concentrations, CW145 (20 ⁇ ), CW168 (20 ⁇ ) or CW254 (50 ⁇ ), there is small decrease in cell viability showing -65% with CW145. However there is negligible effect seen with CW168 and CW254 showing -120% relative growth with each drug alone. Further, treatment with two drug combinations at the said concentrations resulted in better effect seen on cell survival , showing -40% relative growth in case of CW145 (20 ⁇ ) and CW168 (20 ⁇ ) combination and -57% relative growth in case of CW145 (20 ⁇ ) and CW254 (50 ⁇ ) combination. Insignificant decrease in relative growth was seen with CW168 (20 ⁇ ) and CW254 (5() ⁇ ) combination, being -83% relative growth, incubation of the cells with the three drugs in combination at the same concentrations showed drastic effect with relative growth of about 30%.
  • the U87 human glioma cell line is procured from ATCC (American Type Culture Collection, Manassas, VA, ATCC *' HTB-14 ' " ), The cells are resuspended in a media containing 10% FBS (Gibco lot# 1259720) and 4X Gentamicin followed by transferring about 100 ul to each well in an assay plate (3,000 cells/well; passage# 10), DMSO, Digitoxin and drugs (CW145, CW 168 and CW254 individually and in combinations) are serial diluted in an assay media. 100 ⁇ /well of the diluted sample is added to assay plate containing resuspended cells.
  • Final assay volume of each well is about 200 ⁇ , containing 10% FBS, 2X Gentamicin, DMSO, Digitoxin and drugs.
  • the assay plate is incubated for about 71 hours followed by addition of about 20 ⁇ of Promega Substrate CellTiter 96 Aqueous One Solution Reagent to each well. It is incubated at 37°C and absorbance of the sample is read at about 490 nm.
  • Figure 10 illustrates that when the cells are incubated with the each of the drugs alone at the indicated concentrations, CW145 (20 ⁇ ), CW 168 (20 ⁇ ) or CW254 (50 ⁇ ), there is insignificant decrease in cell viability showing -80% with CW145. However there is no effect seen with CW168 and CW254, showing -100% relative growth with each drug alone. Further, treatment with two drug combinations at the said concentrations resulted in better effect seen on cell survival , showing -70% relative growth in case of CW145(20 ⁇ ) and CW168 (20 ⁇ ) combination . -80% relative growth in case of CW145 (20 ⁇ ) and CW254 (50 ⁇ ) combination and also in case of CW168 (20 ⁇ ) and C W254 (50 ⁇ ) combination. Incubation of the cells with the three drugs in combination at the same concentrations showed drastic effect with relative growth of about 60%.
  • U251MG human glioma cell line is procured from Sigma-Aldrich (Catalog number: 09063001 ).
  • PTEN WT LN229 cell line is procured from ATCC (American Type Culture Collection, Manassas, VA, ATCC® CRL-2611 " ).
  • the cells are resuspended in a media containing 10% FBS (Gibco lot# 1259720) and 4X Gentamicin followed by transferring about 100 ul to each well in an assay plate (3,100 cells/well; passage# 6).
  • DMSO, Digitoxin and drugs are serial diluted in an assay media.
  • Figure 11 illustrates the comparison of the effect of the combination in PTEN Null U251 Cells and PTEN WT LN229 cells when combined at the same concentration of CW145 at 15 ⁇ , CW168 at 20 ⁇ and CW254 at 50 uM.
  • the reduction with the 2 dimensional and 3 dimensional combinations are much higher in PTEN Null U251 cells when compared to PTEN WT LN229 cells.
  • With the combination of the 3 drugs there is a synergistic relative growth reduction of -40% in PTEN Null U251 cells while the relative growth reduction in the PTEN WT LN229 cells is only about 20%>,

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Abstract

The present disclosure relates to a pharmaceutical composition and a kit to treat cancer. The disclosure provides a composition comprising AKT inhibitor and at least one of cyclooxygenase-2 inhibitor and 5-lipoxygenase inhibitor. The disclosure further relates to a process of preparing the said composition and a method of treating cancer comprising PTEN mutation/AKT mutation/ PI3K mutation alone or in combination with each other or in combination with mutations in other genes causing cancer.

Description

"A COMPOSITION, PROCESS OF PREPARATION OF SAID
COMPOSITION, KIT AND A METHOD OF TREATING CANCER'
TECHNICAL FIELD
The present disclosure relates to a composition and a kit to treat cancer. Particularly, the disclosure provides a composition comprising AKT inhibitor and atleast one of Cyclooxygenase-2 inhibitor and 5-lipoxygenase inhibitor. The disclosure further relates to a process of preparing said composition and a method of treating cancer where PDK/AKT/mTOR signaling axis is highly activated such as tumors carrying mutation of PTEN/ PBK/AKT individually or in combination with each other or in combination with mutation in other genes causing cancer.
BACKGROUND OF THE DISCLOSURE
Phosphatase and Tensin Homolog or PTEN is a tumor suppressor gene. It is also known as mutated in multiple advanced cancer 1 (MMAC1). It is one of the most commonly mutated of all tumour suppressor genes, and if not mutated, it is often suppressed or downregulated. Somatic PTEN mutations and deletions, and inactivation of PTEN by methylation or microRNA silencing, are common in multiple tumour types. PTEN hamartoma tumour syndrome (PHTS) is a group of syndromes characterized by benign growths and a high risk for cancers of the breast, endometrium and thyroid. Cowden syndrome is the best characterized of these and 85% of patients have germline PTEN mutations. The range of abnormalities in patients with PHTS varies from patient to patient. Tumors associated with alteration of PTEN gene include the classical PHTS-associated tumours like breast, endometrium and thyroid, and also tumours of the central nervous system, prostate, lung, pancreas, liver and adrenal glands, as well as melanoma, leukaemia and lymphoma. An analysis of PTEN gene alteration in different cancer from COSMIC website is below:
Figure imgf000002_0001
Prostate 40
Skin 25
Testis ?5
Biliary tract 20
Urinary tract 16.67
Breast 16.28
Kidney 14.29
Ovary 13.64
Haematopoietic and lymphoid tissue 11.9
Soft tissue 11.11
Lung 9.21
Thyroid 9.09
Bone 8.82
Cervix 7.69
Stomach 4.76
Upper aerodigestive tract 4.55
Autonomic ganglia 3.03
Large intestine 2.63
PTEN is a phosphatase and its lipid phosphatase activity dephosphorylates the 3- phosphoinositide products of PI3K. 3-phosphoinositides can activate important survival kinases, such as phosphoinositide-dependent kinase 1 (PDK1; encoded by PDPK1 ) and AKT. Change in the phosphatase activity or deletion/downregulation of PTEN gene will result in hyper-activated AKT signalling. Hyper activation of AKT can also result due to mutations in PI3KCA and AKT genes. This hyper-activated AKT signalling will affect different processes such as cell cycle progression, metabolism, migration, apoptosis, transcription and translation. Highly activated AKT also confers resistance to different chemotherapy. PTEN mutation is also associated with the resistance to different targeted therapies, for example PTEN is associated with resistance to anti-HER2 therapy and anti-EGFR therapy in Breast cancer and colorectal cancer respectively, PTEN mutated cells have also been shown to give resistance to MEK inhibitors in KRAS mutated cells, Though preclinical studies have shown that m'TOR inhibitors as single agents have shown preclinical success in PTEN mutated profiles, in clinical trial these inhibitor have shown limited efficacy and evidences are less of PTEN mutation and mTOR inhibitor sensitivity
(Fleming et.al. "Phase II trialof temsirolimus in patients with metastatic breast cancer". Breast Cancer ResTreat. 2012 Nov;136(2):355-63. doi: 10.1007/sl0549-011- 1910-7. Epub 2012 Jan 13. PMID: 22245973)
Thus, as observed above, the existing standard of care does not work on a large section of patients harboring mutations in the PTEN/PDKCA/AKT gene. Even chemotherapy has not been found to be effective on these tumors. Single agent therapies have been used as therapies or suggested for use as therapies for cancer treatment for the purpose of improving one or more undesirable symptoms associated with the disease states or for slowing the progression (worsening) of the symptoms. However, the success achieved with the attempted doses of single agents has been limited, and the obstacles to increasing the doses include legitimate concerns about exceeding the therapeutic windows and/or concerns about the manifestation of undesirable side effects at higher doses. Improved treatment protocols for this complex and devastating disorder especially in the subset of tumors harboring PTEN/PDKCA/AKT and other mutations, are greatly needed. A safe and effective treatment that could alleviate suffering and improve outcomes would be a significant medical advance for cancer treatment and potentially for the treatment of other end- stage diseases as well.
The present disclosure aims to overcome the drawbacks of the prior art by providing a composition comprising combination of compounds.
STATEMENT OF THE DISCLOSURE
Accordingly, the present disclosure relates to a composition comprising: i) an AKT inhibitor, and ii) at least one of cyclooxygenase-2 inhibitor and 5 -lipoxygenase inhibitor, optionally along with a pharmaceutically acceptable excipient; a process of preparing the composition said process comprising act of: combining an AKT inhibitor and atleast one of Cyclooxygenase-2 inhibitor and 5 -lipoxygenase inhibitor optionally along with a pharmaceutically acceptable in any ratio, any concentration or any order thereof excipient to obtain the composition; a kit comprising: i) an AKT inhibitor and ii) atleast one of Cyclooxygenase-2 inhibitor and 5 -lipoxygenase inhibitor, optionally along with a pharmaceutically acceptable excipient; a method of treating cancer and associated conditions in a subject in need thereof, the method comprising administering to a subject a composition comprising: i) a therapeutically- effective amount of an AKT inhibitor, and ii) a fherapeutically-effective amount of atleast one of Cyclooxygenase-2 inhibitor and 5 -lipoxygenase inhibitor, optionally along with a pharmaceutically acceptable excipient, wherein the administration uses one or a plurality of dosage forms; use of a composition comprising i) an AKT inhibitor and ii) at least one of cyclooxygenase-2 inhibitor and 5 -lipoxygenase inhibitor, optionally along with a pharmaceutically acceptable excipient in the preparation of a medicament for the treatment of cancer and associated conditions; and a method of inhibiting cancer cells/inducing cytotoxicity in cancer cells/ modulating markers in cancer cells, said method comprising act of contacting the cancer cells with a composition comprising: i) an AKT inhibitor, and ii) atleast one of Cyclooxygenase-2 inhibitor and 5 -lipoxygenase inhibitor, optionally along with a pharmaceutically acceptable excipient.
BRIEF DESCRI PTION OF THE ACCOMPANYING FIGURES Figure 1 depicts the impact of the different combinations of the instant disclosure on a Non-triggered Normal Epithelial Cell. In case of two drag combinations, each drug is taken at a concentration that causes 20% reduction in viability (IC20) calculated based on viability change in PTEN mutated profile. Figure 1.1 depicts the impact of the combination CW145-CW168 on a Non-triggered Normal Epithelial Cell.
Figure 1.2 depicts the impact of the combination CW145-CW254 on a Non-triggi Normal Epithelial Cell. Figure 1.3 depicts the impact of the combination CW145-CW168-CW254 on a Non- triggered Normal Epithelial Cell.
Figure 2 depicts the impact of combinations of the instant disclosure on phenotypic indexes for PTEN Mutated cell lines. Cell lines and the respective profiles include U251 (PTEN and P53 mutant profile) and U87 (PTEN and P53 wild type profile). Here, the U87 cell lines are used as 'control' to assess the effect of the combinations of the instant disclosure on U251 cell line. Figure 2.11 to 2.32 represent effect of combination of two or three drugs on above described cell line profiles. In case of two drag combinations, each drug is taken at a concentration that causes 20% reduction in viability (IC20) calculated based on viability change in PTEN mutated cell line. In case of three-drug combinations (Figure 2.31 and Figure 2.32), each drug is taken at a concentration thai causes 15% reduction in viability (IC15) calculated based on viability change in PTEN mutated cell line.
Figure 2.11 depicts plot of the impact of Single vs. Double combination comprising of drugs CW145 and CW168 at IC20 concentration on viability phenotype in PTEN mutated cell lines. Figure 2.12 depicts plot of the impact of Single vs. Double combination comprising of drags CW145 and CW168 at IC20 concentration on proliferation phenotype in PTEN mutated cell lines.
Figure 2.21 depicts plot of the impact of Single vs. Double combination comprising of drugs CW145 and CW254 at IC20 concentration on viability phenotype in PTEN mutated cell lines.
Figure 2.22 depicts plot of the impact of Single vs. Double combination comprising of drugs CW 145 and CW254 at IC20 concentration on proliferation phenotype in PTEN mutated cell lines.
Figure 2.31 depicts the impact of Single vs. Double vs. Triple combination comprising of drugs CW 145, CW 168 and CW254 at IC15 concentration on viability phenotype in PTEN mutated cell lines. Figure 2.32 depicts the impact of Single vs. Double vs. Triple combination comprising of drags CWT45, CW168 and CW254 at IC15 concentration on proliferation phenotype in PTEN mutated cell lines.
Figure 3 depicts the impact of combinations of the present disclosure on biomarkers for PTEN mutated cell lines. Biomarkers such as apoptotic biomarkers Caspase 3 (CASP3) and PARP1 cleaved; cell cycle checkpoint complexes CDK2-CCNE and CD 4-CCND1 as proliferation biomarkers and biomarkers such as RHEB-GTP and RPS6 downstream of the AKT-niTOR pathway that impact the translation machinery are predictively assayed.
Figure 3.11 depicts the impact of Single vs. Double combination comprising of drugs CW145 and CW168 at IC20 concentration on CASP3, an apoptosis biomarker, in PTEN mutated cell lines.
Figure 3.12 depicts the impact of Single vs. Double combination comprising of drugs CW 145 and CW168 at IC20 concentration on PARP1 Cleaved, an apoptosis biomarker, in PTEN mutated cell lines.
Figure 3.13 depicts the impact of Single vs. Double combination comprising of drugs CW145 and CW168 at IC20 concentration on CDK2-CCNE complex, biomarker for proliferation phenotype, in PTEN mutated cell lines. Figure 3.14 depicts the impact of Single vs. Double combination comprising of drugs CW145 and CW168 at IC20 concentration on CDK4-CCND1 complex, biomarker for proliferation phenotype, in PTEN mutated cell lines.
Figure 3.15 depicts the impact of Single vs. Double combination comprising of drugs CW145 and CW168 at IC20 concentration on RHEB-GTP, biomarker to monitor protein translation, in PTEN mutated cell lines.
Figure 3.16 depicts the impact of Single vs. Double combination comprising of drags CW145 and CW168 at IC20 concentration on RPS6, biomarker to monitor protein translation, in PTEN mutated cell lines. Figure 3.21 depicts the impact of Single vs. Double combination comprising of drugs CW145 and CW254 at IC20 concentration on CASP3 in PTEN mutated cell lines. Figure 3.22 depicts the impact of Single vs. Double combination comprising of drugs CW145 and CW254 at IC20 concentration on PARPl Cleaved in PTEN mutated cell lines.
Figure 3.23 depicts the impact of Single vs. Double combination comprising of drugs CW145 and CW254 at IC20 concentration on CDK2-CCNE complex in PTEN mutated cell lines.
Figure 3.24 depicts the impact of Single vs. Double combination comprising of drugs CW145 and CW254 at IC20 concentration on CDK4-CCND1 complex in PTEN mutated cell lines.
Figure 3.25 depicts the impact of Single vs. Double combination comprising of drugs CW1.45 and CW254 at IC20 concentration on RHEB-GTP in PTEN mutated cell lines.
Figure 3.26 depicts the impact of Single vs. Double combination comprising of drags CW145 and CW254 at IC20 concentration on RPS6 in PTEN mutated cell lines.
Figure 3.31 depicts the impact of Single vs. Double vs. Triple combination comprising of drugs CW145, CW168 and CW254 at IC15 concentration on CASP3 in PTEN mutated cell lines
Figure 3.32 depicts the impact of Single vs. Double vs. Triple combination comprising of drugs CW145, CW168 and CW254 at IC15 concentration on PARPl Cleaved in PTEN mutated cell lines.
Figure 3.33 depicts the impact of Single vs. Double vs. Triple combination comprising of drags CW145, CW168 and CW254 at IC15 concentration on CDK2- CCNE complex in PTEN mutated cell lines. Figure 3.34 depicts the impact of Single vs. Double vs. Triple combination comprising of drugs CW145, CW168 and CW254 at IC15 concentration on CDK4- CCND1 complex in PTEN mutated cell lines. Figure 3.35 depicts the impact of Single vs. Double vs. Triple combination comprising of drags CW145, CW168 and CW254 at IC15 concentration on KHEB- GTP in PTEN mutated cell lines.
Figure 3.36 depicts the impact of Single vs. Double vs. Triple combination comprising of drugs CW145, CW168 and CW254 at IC15 concentration on RPS6 in PTEN mutated cel l lines.
Figure 4 depicts scientific rationale for the diflerent combinations of the present disclosure.
Figure 4.1 depicts scientific rationale for the CW145-CW168 combination.
Figure 4.2 depicts scientific rationale for the CW145-CW254 combination.
Figure 4.3 depicts scientific rationale for the CW145-CW 168-CW254 combination. Figure 5 depicts the impact of variable dosages of the drug as single agent and in combination on key phenotypes - Viability and Proliferation in PTEN mutated cell lines U87 and U251. The drag having variable dosage is CW145, other drugs in combination CW168, and CW254 are kept at fixed dosage equivalent to IC20 in case of two drug combination and IC15 in case of three drug combination,
Figure 5.11 depicts dose response of single drag CW145 with concentration C equal to IC20 and its combination with fixed doses of CW168 at IC20 concentrations having effect on viability index in PTEN mutated cell line -U87. Figure 5.12 depicts dose response of single dr g CW145with concentration C equal to IC20 and its combination with fixed doses of CW168 at IC20 concentrations having effect on proliferation index in PTEN mutated cell line -TJ87.
Figure 5.21 depicts dose response of single drug CW145 with concentration C equal to IC20 and its combination with fixed doses of CW168 at IC20 concentrations having effect on viability index in PTEN mutated cell line -U251.
Figure 5,22 depicts dose response of single drug CW145with concentration C equal to 1C20 and its combination with fixed doses of CW168 at IC20 concentrations having effect on proliferation index in PTEN mutated cell line -U251.
Figure 5.31 depicts dose response of single drug CW145 with concentration C equal to IC20 and its combination with fixed doses of CW254 at IC20 concentrations having effect on viability index in PTEN mutated cell line -U87,
Figure 532 depicts dose response of single drug CW145 with concentration C equal to IC20 and its combination with fixed doses of CW254 at IC20 concentrations having effect on proliferation index in PTEN mutated cell line -U87.
Figure 5.41 depicts dose response of single drug CW145 with concentration C equal to IC20 and its combination with fixed doses of CW254 at IC20 concentrations having effect on viability index in PTEN mutated cell line -U251 . Figure 5.42 depicts dose response of single drug CW145 with concentration C equal to IC20 and its combination with fixed doses of CW254 at IC20 concentrations having effect on proliferation index in PTEN mutated cell line -U251.
Figure 5.51 depicts dose response of single drug CW145 with concentration C equal to 1C15 and its combination with fixed doses of CW'168 and CW254 at 1C15 concentrations having effect on viability index in PTEN mutated cell line -U87.
Figure 5.52 depicts dose response of single drug CW145with concentration C equal to IC15 and its combination with fixed doses of CW168 and CW254 at IC15 concentrations having effect on proliferation index in PTEN mutated cell line -U87,
Figure 5.61 depicts dose response of single drug CW 145 with concentration C equal to IC15 and its combination with fixed doses of CW168 and CW254 at IC15 concentrations having effect on viability index in PTEN mutated cell line -U251. Figure 5,62 depicts dose response of single drug CW145with concentration C equal to IC15 and its combination with fixed doses of CW'168 and CW254 at 1C15 concentrations having effect on proliferation index in PTEN mutated cell line -U251.
Figure 6-11 depicts in-vitro experiments showing the impact of variable dosages of the dnig as single agent and in combination on relative growth in PTEN mutated and PTEN wild-type cell lines. From figure 6 to 8, CW145 tested is MK2206 and from figure 9 to 11, CW145 tested is Nelfinavir,
Figure 6 depicts the percentage change in the relative growth of the PTEN mutated ceil line U251 at single, two and three drag combinations of CW 145. CW168 and CW254. On the x-axis, individul dosage of CW145, CW168 and CW254 are taken at 5, 50 and 100 uM respectively. In combination, 1/10th of CW145 (0.5 μΜ), Half of CW168 (25 μΜ) and Half of CW254 (50 μΜ) concentration is taken.
Figure 7 depicts the percentage change in the relative growth of the PTEN mutated cell line U251 at single, two and three drag combinations of CW 145, CW168 and CW254. On the x-axis, fixed dosage of CW145 (0.5 μΜ) and CW254 (50 μΜ) is taken along with varying dosage of CW168 (25 and 50 μΜ)
Figure 8 depicts the percentage change in the relative growth of the PTEN mutated cell line U87 and PTEN wild type cell line LN229 at single, two and three drag combinations of CW145, CW168 and CW254, On the x-axis, fixed dosage of CW145, CW168 and CW254 are taken at 0.5, 25 and 50 μΜ respectively.
Figure 9 depicts the percentage change in the relative growth of the PTEN mutated cell line U251 at single, two and three dr g combinations of CW145, CW168 and CW254. On the x-axis, fixed dosage of CW145, CW168 and CW254 are taken at 20, 20 and 50 μΜ respectively.
Figure 10 depicts the percentage change in the relative growth of the PTE mutated cell line U87 at single, two and three drug combinations of CW 145, CW168 and CW254. On the x-axis, fixed dosage of CW145, CW168 and CW254 are taken at 20, 20 and 50 μΜ respectively.
Figure 11 depicts the percentage change in the relative growth of the PTEN mutated cell line U251 and PTEN wild type cell line LN229 at single, two and three drug combinations of CW145, CW168 and CW254. On the x-axis, fixed dosage of CW145, CW168 and CW254 are taken at 15, 20 and 50 μΜ respectively.
DETAILED DESCRIPTION OF THE DISCLOSURE
The present disclosure provides multi -targeted combination therapeutic approach to suppress and cure symptoms associated with Cancers and associated conditions. The dnig combinations were validated using Virtual Tumor Cell Platform and cell line experiments as described herein.
The present disclosure provides two, and three drag combinations, which provide multi-targeted combination therapeutic approach to suppress and cure symptoms associated with PTEN/PDKCA/AKT mutant Cancers and associated conditions, wherein the Cancer is associated with mutation in PTEN/PDKCA/AKT alone or in combination with each other or in combination with other genes causing cancer. The drag combinations were validated using cell line experiments in human glioma cell lines- U251MG and U87 as described herein.
In an embodiment, the present disclosure focuses on PTEN/PD /AKT mutant tumors irrespective of tissue subtype or origin, with PTEN-PDK-AKT pathway being the predominant driver in the cancer cell. The main focus of the present disclosure is to study the biochemical dynamics of cancers carrying mutations in PTEN/PDK/AKT and design therapies that are effective in this aggressive untreatable subset of cancers.
In an embodiment of the present disclosure, the two and three -drag combinations provide synergistic efficacy on the end-point markers, while dosing is as low as 1 /4, 1/3 or 1/2 of the recommended therapeutic dose of the drag in humans. Using a lower dose of the individual drag also provides an advantage in terms of minimizing the intensity of side-effects or toxicities associated with the drags. Also, the drug combination works by inhibiting multiple targets minimally, so that an amplified effect is observed on all of the primary end-point markers and at the same time ensuring that all the targets have primary response ability, so as to negate the possibility of immune suppression and secondary infections.
In an embodiment of the present disclosure, use of smaller doses of individual drugs also lower the cost of manufacture and formulation, providing an improved effect at lower price to the subject. Smaller doses also mitigate wasteful administration of a drag to a physiological system that has been saturated or has reached a peak therapeutic response from smaller, synergistic doses, In an embodiment, the important advantages provided by the compounds, compositions, methods and uses of the present disclosure are:
® reduction of dosages of drugs/compounds being used in the treatment of cancers caused due to PTEN/AKT/PBK mutations individually or in combination with each other or in combination with other gene mutations;
* synergistic efficacy of the combination of compounds provided for management of cancers caused due to PTEN/AKT/PBK mutations individually or in combination with each other or in combination with other gene mutations; and
• minimizing the intensity of side-effects or toxicities associated with the drugs used in the treatment of cancers caused due to PTEN/AKT/PBK mutations individually or in combination with each other or in combination with other gene mutations.
As described herein, the compounds used in the the composition of the instant disclosure is alternatively referred as "pharmaceutical composition", "compound(s)", "drug(s)", "inhibitors" throughout the specification. Further, reference to combination of 2 drug(s)/compound(s) are alternatively made as "2 drag Combination", "2D" and reference to combination of 3 drug(s)/compound(s) are alternatively made as "3 drag Combination", "3D" throughout the specification, As referred throughout the specification, the term "mutation" includes deletion, insertion, amplification of a gene etc.
The present disclosure relates to a composition comprising: i) an AKT inhibitor; and ii) at least one of cyclooxygenase-2 inhibitor and 5-lipoxygenase inhibitor; optionally along with a pharmaceutically acceptable excipient.
The present disclosure also relates to a process of preparing a composition comprising: i, an AKT inhibitor; and ii, atleast one of Cyclooxygenase-2 inhibitor and 5-lipoxygenase inhibitor; optionally along with a pharmaceutically acceptable excipient, said process comprising act of: combining an AKT inhibitor and atleast one of Cyclooxygenase-2 inhibitor and 5-lipoxygenase inhibitor optionally along with a pharmaceutically acceptable excipient, in any ratio, any concentration or any order thereof.
The present disclosure also relates to kit comprising: i. an AKT inhibitor; and ii. atleast one of Cyclooxygenase-2 inhibitor and 5-lipoxygenase inhibitor; optionally along with a pharmaceutically acceptable excipient.
The present disclosure also relates to a method of treating cancer and associated conditions in a subject in need thereof, the method comprising administering to a subject a composition comprising: i) a therapeutically-effective amount of an AKT inhibitor; and
ii) a therapeutically-effective amount of atleast one of Cyclooxygenase-2 inhibitor and 5-lipoxygenase inhibitor;
optionally along with a pharmaceutically acceptable excipient, wherein the administration uses one or a plurality of dosage forms. The present disclosure also relates to use of a composition comprising: i) an AKT inhibitor; and ii) atleast one of Cyclooxygenase-2 inhibitor and 5-lipoxygenase inhibitor; optionally along with a pharmaceutically acceptable excipient in the preparation of a medicament for the treatment of cancer and associated conditions. In an embodiment of the present disclosure, the AKT inhibitor is a direct or indirect inhibitor.
In another embodiment of the present disclosure, the AKT inhibitor is a direct inhibitor when it binds to AKT thereby causing inhibition whereas an indirect inhibitor causes inhibition of AKT through the inhibition of other proteins, These proteins may be involved in AKT pathway or may be any protein whose inhibition leads to inhibition of AKT,
In another embodiment of the present disclosure, AKT inhibitor is an indirect inhibitor which inhibits AKT and also inhibits other proteins involved in the same disease condition or a different disease condition.
In yet an embodiment of the present disclosure, the composition comprises an AKT inhibitor and cyclooxygenase-2 inhibitor optionally along with a pharmaceutically acceptable excipient.
In still another embodiment of the present disclosure, the composition comprises an AKT inhibitor and 5-lipoxygenase inhibitor optionally along with a pharmaceutically acceptable excipient.
In still another embodiment of the present disclosure, the composition comprises an AKT inhibitor, cyclooxygenase-2 inhibitor and 5-lipoxygenase inhibitor optionally along with a pharmaceutically acceptable excipient. In still another embodiment of the present disclosure, the AKT inhibitor is selected from a group comprising compound of:
Formula 1(a):
Figure imgf000015_0001
wherein R is halogen, Rl and R2 are alkyl or hydrogen
Formula 1(b):
Figure imgf000016_0001
wherein R3, R4, R5, R6 are hydrogen or alkyl
Formula 1(c):
Figure imgf000016_0002
wherein R7, R8, R9, RIO, Rl 1 , R12 are alkyl or hydrogen
Formula 1(d):
Figure imgf000017_0001
wherein R13, R14 are alkyl or hydrogen, R15 is halo
Formula 1(e):
Figure imgf000017_0002
wherein R16, R17, R18 are alkyl or hydrogen, R19 is halogen
Formula 1(f):
Figure imgf000017_0003
wherein R20 is halogen, R21 , R22, R23 are alkyl or hydrogen
Formula 1(g):
Figure imgf000018_0001
wherein R24, R25, R26, R27, R29 are alkyl or hydrogen, R28 is halogen Formula 1(h):
Figure imgf000018_0002
wherein R30, R31 ,R33, R35, R36 are alkyl or hydrogen; R32, R34 are alkyl
Formula l (i):
Figure imgf000019_0001
wherein R37, R38, R39 are alkyl or hydrogen Formula l(j):
Figure imgf000019_0002
wherein R40, R41 , R42 are alkyl or hydrogen
Formula l(k):
Figure imgf000019_0003
wherein R43, R44 are alkyl or hydrogen Formula 1(1):
Figure imgf000020_0001
wherein R45, R46, R47, R48, R49, R50 are alkyl or hydrogen
Formula l(m):
Figure imgf000020_0002
wherein R51, R52, R53, R54,R56 are alkyl or hydrogen; R55 is halogen Formula l(n):
Figure imgf000021_0001
Zl, Z2, 73, Z4, Z5,Z6,Z7, Z8, Z9, Z10 are alkyl or hydrogen Formula l(p):
Figure imgf000022_0001
wherein Zl l, Z12, Z13, Z14, Z15, Z16 are alkyl or hydrogen Formula l(q):
Figure imgf000022_0002
wherein Z17, Z19, Z20, Z21 are alkyl or hydrogen; Z18 is halogen Formula l(r):
Figure imgf000023_0001
wherein Z22, Z23, Z24, Z25, Z26, Z27 and Z28 are alkyi or hydrogen Formula l(s):
Figure imgf000023_0002
wherein Z29, Z30, Z31 , Z32, Z33, Z34, Z35, Z36, Z37, Z38, Z39 are alkyi or hydrogen
Formula l(t):
Figure imgf000024_0001
wherein Z48, Z49, Z50, Z51, Z52, Z53, Z54 are alkyl or hydrogen
Formula l(v):
Figure imgf000025_0001
wherein Z55, Z56, Z57, Z58, Z59, Z60, Z61 are hydrogen or alkyl Formula l(w):
Figure imgf000025_0002
wherein Z62, Z63, Z64, Z65, Z66, Z67, Z68 are hydrogen or alkyl Formula l(x):
Figure imgf000026_0001
wherein Z69, Z70, Z71, Z72, Z73, Z74, Z75, Z76, Z77 are Hydrogen or Alkyl Formula l (y):
Figure imgf000026_0002
wherein Z78, Z79, Z80, Z81 , Z82, Z83 are alkyl or hydrogen; a pharmaceutically-acceptable salt of any of the foregoing and combination thereof.
In still another embodiment of the present disclosure, the AKT inhibitor selected from a group comprising compounds of formula l(o), l(p), l(q), l(r), l(s), l(t), l(u), l(v), l (w), ] (x) and l(y) is also an HIV protease inhibitor. In still another embodiment of the present disclosure, the Cyclooxygenase-2 inhibitor is selected from a group comprising compounds of:
Formula 2(a):
Figure imgf000027_0001
wherein XI , X2 and X3 are hydrogen or alkyl; X is halogen
Formula 2(b):
Figure imgf000027_0002
wherein X4 and X5 are hydrogen or alkyl
Formula 2(c):
Figure imgf000028_0001
wherein X6. X7 are alkvl or hydrogen
Formula 2(d):
Figure imgf000028_0002
wherein X8 is halogen; X9, X10, Xl l are alkvl or hydrogen
Formula 2(e):
Figure imgf000028_0003
wherein XI 2, XI 3 are alkvl or hydrogen; X14 is halogen
Formula 2(f):
Figure imgf000029_0001
wherein X17, X18, X19, X20 are alkyl or hydrogen
Formula 2(h):
Figure imgf000029_0002
wherein X21 is halogen; X22, X23, X24 are alkyl or hydrogen Formula 2(i):
Figure imgf000030_0001
wherein X25 is halogen, X26, X27 are alkyl or hydrogen Formula 2(j):
Figure imgf000030_0002
wherein X28 is halogen; X29, X30, X31 are alkyl or hydrogen
Formula 2(k):
Figure imgf000030_0003
wherein X32, X33, X34 are alkyl or hydrogen
Formula 2(1):
Figure imgf000031_0001
wherein X35, X36, X37 are alkyl or hydrogen
Formula 2(m):
Figure imgf000031_0002
wherein X38 is halogen, X39,X40, X41 are alkyl or hydrogen
Formula 2(n):
Figure imgf000031_0003
wherein X42, X43 are hydrogen or alkyl
Formula 2(o):
Figure imgf000032_0001
wherein X46, X47 are alkyl or hydrogen
Formula 2(q):
Figure imgf000032_0002
wherein X48, X49 are alkyl or hydrogen; X50 is halogen Formula 2(r):
Figure imgf000033_0001
wherein X51is cycloalkyi or aryl; X52, X53 are alkyl or hydrogen
Formul a 2(s):
Figure imgf000033_0002
erein X54, X55, X56 are alkyl or hydro
Formula 2(t):
Figure imgf000033_0003
wherein X57, X58, X59, X60, X61 are alkyl or hydrogen
Formula 2(u):
Figure imgf000034_0001
wherein X62 is alkyl or hydrogen
Formula 2(v):
Figure imgf000034_0002
wherein X63, X64 are halogen; X65 is selected from alkoxy, alkyl sulfonyl and hydrogen
Formula 2(w):
Figure imgf000035_0001
wherein X66, X67, X68, X69 are alkyl or hydrogen and X70 is halogen
Formula 2(x):
Figure imgf000035_0002
wherein X71 is halogen and X72 is alley! or hydrogen
Formul a 2(y):
Figure imgf000036_0001
wherein X73, X74, X75 are hydrogen or alkyl and X76 is halogen
Formula 2(z):
Figure imgf000036_0002
wherein X77, X78, X79 are alkyl or hydrogen
Formula 2(al ):
Figure imgf000036_0003
wherein X80, X81, X82 are alkyl or hydrogen; X83 is halogen;
a pharmaceutically-acceptable salt of any of the foregoing and combination thereof. In still another embodiment of the present disclosure, the 5-lipoxygenase inhibitor is selected from a group comprising compounds of:
Formula 3(a):
Figure imgf000037_0001
wherein Yl is alky! or hydrogen
Formula 3(b):
Figure imgf000037_0002
wherein Y2, Y3, Y4, Y5, Y7, Y 8 are alkyl or hydrogen; Y6 is halogen
Formula 3(c):
Figure imgf000038_0001
wherein Yl l is halogen; Y9, Y10, Y12, Y13, Y14 are alkyl or hydrogen Formula 3(d):
Figure imgf000038_0002
wherein Y15 is hydrogen or alkyl
Formula 3(e):
Figure imgf000038_0003
wherein Y16, Y17, Y 18, Y19 are alkyl or hydrogen
Formula 3(f):
Figure imgf000039_0001
wherein Y20, Y21 are alkyl or hydrogen Formula 3(g):
Figure imgf000039_0002
wherein Y22, Y23,Y24, Y25 are aikyi or hydrogen; a pharmaceutically-acceptable salt of any of the foregoing and combination thereof,
In yet another embodiment of the present disclosure, the pharmaceutically-acceptable excipient is a granulating agent, binding agent, lubricating agent, disintegrating agent, sweetening agent, glidant, anti-adherent, anti-static agent, surfactant, anti -oxidant, gum, coating agent, coloring agent, flavouring agent, coating agent, plasticizer, preservative, suspending agent, emulsifying agent, plant cellulosic material, spheronization agent, immediate release agent, controlled release agent, sustained delayed release agent or combination thereof.
In yet another embodiment of the present disclosure, the composition is in a dosage form selected from a group comprising feed, food, pellet, lozenge, liquid, elixir, aerosol, inhalant, spray, powder, tablet, pill, capsule, gel, geltab, nanosuspension, nanoparticle, microgel, suppository troches, aqueous or oily suspensions, ointment, patch, lotion, dentifrice, emulsion, cream, drop, dispersible powder or granule, emulsion in hard or soft gel capsule, syrup, phytoceutical, nutraceutical and combination thereof. In yet another embodiment of the present disclosure, the composition is a dosage form having an immediate release, a controlled release or a sustained delayed release mechanism.
In yet another embodiment of the present disclosure, the composition is a dosage form formulated for mode of administration selected from a group comprising intravenous, subcutaneous, intramuscular, oral, rectal, aerosol, parenteral, ophthalmic, pulmonary, transdermal, vaginal, otic, nasal, topical administration and combination thereof.
In an embodiment of the present disclosure, the cancer and associated conditions are caused by mutation in PTE /PBK/AKT alone or in combination with each other or in combination with mutation in other genes causing cancer.
In another embodiment of the present disclosure, the cancer is selected from a group comprising glioblastoma multiforme, endometrial cancer, ovarian cancer, prostate cancer, breast cancer, lung cancer, colorectal cancer, pancreatic cancer, brain cancer, head and neck cancer, glioblastoma, multiple myeloma, acute non lymphocytic leukemia and myelodysplasia, or any combination of conditions thereof.
In yet another embodiment of the present disclosure, the therapeutically effective amount of the AKT inhibitor is from about 10% to about 100% of a maximum tolerated dose; the therapeutically effective amount of the cyclooxygenase-2 inhibitor is from about 10% to about 100% of a maximum tolerated dose; and the therapeutically effective amount of the 5-lipoxygenase inhibitor is from about 10% to about 100%) of a maximum tolerated dose. In still another embodiment of the present disclosure, the therapeutically effective amount of the AKT inhibitor is from about I mg to about 3000 mg; the therapeutically effective amount of the cyclooxygenase-2 inhibitor is from about 1 mg to about 3000 mg; and the therapeutically effective amount of the 5-lipoxygenase inhibitor is from about 1 mg to about 3000 mg.
The present disclosure also relates to a method of inhibiting cancer cells/inducing cytotoxicity in cancer cells/ modulating markers in cancer cells, said method comprising act of contacting the cancer cells with a composition comprising: i. an AKT inhibitor; and ii. atleast one of Cyclooxygenase-2 inhibitor and 5 -lipoxygenase inhibitor; optionally along with a pharmaceutically acceptable excipient. In an embodiment of the present disclosure, the method of inhibiting cancer cells/ inducing cytotoxicity in cancer ceils/ modulating markers in cancer cells include methods of reducing/inhibiting proliferation of cancer cells, methods of reducing/inhibiting viability of cancer cells nducing apoptosis of cancer cells etc.
In another embodiment of the present disclosure, modulating the markers in cancer cells include increasing/decreasing the levels of certain markers in cancer cells.
In an embodiment of the present disclosure, the AKT inhibitors belong to a class of anti-cancer agents or HIV protease inhibitors or a combination thereof, Cyclooxygenase-2 inhibitors belong to a class of non-steroidal anti-inflammatory agents (NSAID) and 5-lipoxygenase inhibitors belong to a class of anti-asthmatic agents.
In still another embodiment of the present disclosure, said cancer/condition is any cancer with PTEN/PI3K/AKT mutation individually or in combination with each other or in combination with mutation in other genes. The said cancer is any cancer including, but not limiting to, cancers of the central nervous system such as glioblastoma multiforme, endometrial cancer, ovarian cancer, prostate cancer, breast cancer, pancreatic cancer, colorectal cancer, lung cancer, head and neck cancer, multiple myeloma, acute non lymphocytic leukemia or myelodysplasia, or any combination of conditions thereof, or any condition having a mutation therein.
In still another embodiment of the present disclosure, said mutation is a PTEN gene mutation or PI3K. gene mutation or AKT gene mutation in combination with other gene mutations that support cancer, selected but not restricted to a group comprising EGFR, RAS, B-catenin, CDKN2A, P13KCA, APC, MYC, BCL2, SOCS1, TP53and SMAD4 or any combination thereof. In an embodiment, the present disclosure provides a composition comprising a combination of AKT inhibitor and atleast one of Cyclooxygenase-2 inhibitor and a 5- lipoxygenase inhibitoralong with pharmaceutically acceptable excipients. In an embodiment, the present disclosure provides a kit comprising a composition of AKT inhibitor and atleast one of Cyclooxygenase-2 inhibitor and a 5 -lipoxygenase inhibitor along with pharmaceutically acceptable excipients, wherein the kit comprises one or a plurality of dosage forms, AKT inhibiting compounds- CW145:
CW145class of drug is an inhibitor of AKT or specific inhibitor of HIV protease that also inhibits AKT, HIV protease inhibitors are orally available drugs developed to specifically inhibit the HIV aspartyl protease, a retroviral enzyme that cleaves the viral gag-pol polyprotein necessary for the production of infectious viral particles and that lacks mammalian close homologs. These drags are approved for anti-viral therapy for HIV infected patients. However, it was determined that these drugs can cause insulin resistance that was determined to be due to inhibition of AKT signaling. Clinical studies demonstrated that HIV positive patients receiving these drags had an inhibition of their phosphorylated AKT levels. Thus, these drags were tested in tumor cells and found to demonstrate anti-neoplastic effect, primarily through their inhibition of AKT. Besides AKT inhibition, a few of the drags from this class of compounds have been shown to moderately inhibit the proteasomal activity and cause ER stress but only at very high concentrations of the compound. AKT inhibition and anti-neoplastic activity is achieved at the CMax concentrations obtained with the approved dose range.AKT is highly activated in PTEN mutated or PTEN null profiles or PI3KCA mutant or AKT mutant profiles. PTEN is a tumor suppressor gene which carries out the dephosphorylation of PIP3 to PIP2, leading to inactivation of AKT/mTOR signaling pathway. PTEN mutation or PTEN loss results in accumulation of PIP3 which in turn activates AKT and PDK1. PDK1 carries out further phosphorylation and activation of AKT. AKT can be highly activated with PI3KCA mutation or AKT mutation. The constitutively activated AKT drives cell survival, proliferation and cellular metabolism through its downstream signaling such as inhibitory phosphorylation of downstream pro-apoptotic proteins like FO.XO, GSK3B etc, activation of mTORCl which phosphorylates p70 ribosomal protein S6 kinase (S6K) and eukaryotic translation-initiation factor 4E (eIF4E)-binding protein 1 (4EBP1) to activate protein translation and cell proliferation. mTORCl further activates HIF1 which is a key transcription factor for many cellular metabolism genes and also plays an important role in angiogenesis.
Hence, CW145 causes growth inhibition of PTEN mutated or PTEN null or PI3KCA mutant or AKT mutant profiles having constitutively activated AKT. However, with AKT inhibition, the negative feedback loop from mTOR on AKT via IRS1 becomes weak thereby reducing the overall inhibition on AKT and hence increased concentration of the drug is needed to abrogate complete AKT signaling. Such high concentration of the drug may be toxic for the normal and healthy cells also.
COX-2 inhibiting compounds- C 168:
CW168 class of drug is an inhibitor of COX-2 which is reported to have high expression levels in PTEN profiles via the AKT - NF-kB~ COX2 transcription. Inhibition of COX-2 will also result in reduced levels of prostaglandins like PGE2, PGI2 and PGD2, thereby reducing the GPCR mediated activation of ΡΒΚβ by these prostaglandins farther augmenting the effect of CW 145. ΡΟΚβ activity has been reported to be high in PTEN profiles and hence the above inhibition will make the combination more specific to profiles harboring PTEN mutation or loss. CW168 will also help in reducing the pro-angiogenic effect of prostaglandins.
The combination of any compound CW145 and any compound CW168 in any amount, ratio, concentration, or order thereof inhibit upregulated AKT signaling and COX-2 signaling in PTEN null/mutated profiles. The combination is specific for PTEN null/mutated profiles or PI3K/AKT mutated/amplified profiles where the expression of COX-2 is mainly driven by ΑΚΤ/ΝΡΚβ pathway and not ERK/p38. Also, in such profiles the RAS/RAF/ERK pathway axis is not dominant. Therefore, in these profiles, although inhibition of AKT will relieve the negative feedback of AKT on RAF, p38 and JNK and consequently will increase their activation, this will not have any negative effect because the overall process of tumorigenesis would be driven by AKT mediated signaling and not via the RAS-RAF-MEK signaling axis.
On the contrary, in case of PTEN wild type and high MEK signaling profiles, this combination will not be therapeutically effective. Using CW145 in these profiles may still have some effect; however in combination with CW168, this therapeutic effect would be lost probably as per the mechanism explained below. CW145can activate ERK, p38 and JNK by relieving inhibitory effect of AKT on these kinases. Activated ERK, p38 and JNK will increase API and NF-kB signaling which in turn may upregulate COX-2 expression. This high COX-2 expression will lead to increase in GPCR signaling. High GPCR will increase cAMP level which in turn will activate PKA, PKA is known to inhibit RAF signaling and thus will compensate AKT negative feedback on RAF. So CW145 alone in PTEN wild-type profiles may show significant effect by upregulation of COX2/GPCR/PKA pathway which will keep in check the over-activation of ERK pathway. However, presence of CW168 in combination of CW145 will release this dual inhibition of AKT and PKA on RAF resulting in high ERK signaling. This may have a negative therapeutic impact as the pathway driving tumorigenesis in such profiles would be increasing. Thus, these profiles will show resistance to this combination.
ALOX-5 inhibiting compounds:
CW254 class of drug is an ALOX5 inhibitor. ALOX5 expression is reported to be high in PTEN mutant/null profiles, via AKT ~> NFKB~> ALOX5 transcription. Inhibition of ALOX5 will also result in reduced levels of leukotrienes like LTB4, LTC4, LTD4 and LTE4 thereby, reducing the GPCR mediated activation of ΡΙ3Κβ by these leukotrienes further augmenting the effect of CW145. ΡΓ3Κβ activity has been reported to be high in PTEN profiles and hence the above inhibition will make the combination of CW145 and CW254 more specific to profiles harboring PTEN mutation or loss.
The combination of any compound CW145 and any compound CW254 in any amount, ratio, concentration, or order thereof inhibit upregulated AKT signaling and ALOX5 signaling in PTEN null/mutated profiles. The combination affect highly upregulated PI3K/AKT pathway by attacking it from two sides. One is the direct inhibition of AKT and another is inhibition of I' 13 K B signaling via down regulation of GPCR. This strategic combination reduces the actual concentration of single agents without compromising efficacy on PI3K/AKT pathway. Lower dosage also reduces the unwanted toxicities. In addition, the combination also reduces angiogenesis process by inhibiting leukotriene pathway,
The combination of any compound CW145, any compound CW168 and any compound CW254 in any amount, ratio, concentrat on, or order thereof synergistically inhibits the GPCR signaling and PI3K/AKT signaling pathway, Arachidonic acid acts as a substrate for COX and LOX pathway. Simultaneous inhibition of both COX and LOX pathway synergistically decreases GPCR signaling and angiogenesis,
The synergistic efficacy of the combination of compounds is to be analyzed by the parameter that two or more mutually exclusive compounds, which are different in functions and characteristics and that act via different pathways, work in combination with each other and provide a reduction in the proliferation of cells which is higher than the reduction brought about by the compounds individually. Thus, the compositions of the present disclosure provide a surprising advantage over the individual compounds.
The present disclosure relates to combination of any compound CW145and atleast one of any compound CW168 and any compound CW254 in any amount, ratio, concentration, or order thereof which synergistically inhibits the PI3 /AKT signaling pathway, the GPCR mediated activation of ΡΙ3Κβ and PDKy and in turn causes downstream activation of AKT and activate the AMPK mediated inhibition of mTOR pathway.
In an embodimeni of the present disclosure, the CW145 class of drugs are anti-cancer agents and they function as AKT inhibitor and/or HIV protease inihibitors.
In another embodiment of the present disclosure, the CW168 class of drugs are non- steroidal anti -inflammatory drugs (NSAID) and they function as Cyclooxygenase-2 inhibitor.
In another embodiment of the present disclosure, the CW254 class of drugs are antiasthmatic drags and they function as 5 -lipoxygenase inhibitor. As used herein, the term, "CW145168," refers to a combination of any CW145 compound, and any CW 168 compound in any amount, ratio, concentration, or order thereof.
As used herein, the term, "CW145254," refers to a combination of any CW145 compound, and any CW254 compound in any amount, ratio, concentration, or order thereof. As used herein, the term, "CW145168254," refers to a combination of any CW145 compound, any CW168 compound and any CW254 compound in any amount, ratio, concentration, or order thereof.
Non-limiting examples of CW145 include:
a) MK2206 or 8-[4-(l -aminocyclobutyl)phenyl]-9-phenyl-2H-
[l,2,4]triazolo[3,4-f][l,6]naphthyridin-3-one;dihydrochloride b) PERIFOSINE or KRX-0401 or NSC 639966 or D 21266 or (1 ,1 dimethylpiperidin- 1 -ium-4-yl) octadecyl phosphate c) Akt Inhibitor X or 1Q-DEBC HYDROCHLORIDE or 10-(4'-(N- diethyl.amino)butyl)-2-chlorophenoxazine or HC1 or SureCNl 559590 or CTK8E7967 or 201788-90-1 or 4-(2-chlorophenoxazin-10-yl)-N}N- diethylbutan- 1 -amine;hydrochloride d) A-674563 or (2S)-l-[5-(3-methyl-2H-mdazol-5-yl.)pyridin-3-yl]oxy-3- phenylpropan-2-amine e) API 2 or API -2 or Akt Inhibitor V or Triciribine or 5 -methyl- 1 - pentofuranosyi~l,5-dihydro-l,4,5,6,8-pentaazaacenaphthylen-3-amme f) AT 7867 or 4-(4-chlorophenyl)-4-[4-(lH-pyrazol-4-yl)phenyl]piperidine g) CCT128930 or 4-[(4-chlorophenyl)methyl]- 1 -(7H-pyrrolo[2,3 d]pyrimidin-4-yl)piperidin-4-amine h) FPA 124 or Dichloro[(2Z)-2-[(4-oxo-4H-l-benzopyran-3- yl)methylene]hydrazinecarbothioamide i) GDC-Q068 or GDC0068 or BCP9000712 or CS-0975 or RG 7440 or (2S)- 2-(4-chlorophenyl.)-l -[4-[(5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]piperazin-l-yl]-3-(propan-2-ylamino)propan-
1 -one j) GSK690693 or 4-[2-(4-amino-l ,2 or 5-oxadiazol-3-yl)-l-ethyl-7-[[(3S)- piperidin-3-yl]methoxy]imidazo[4,5-c]pyridin-4-yl]-2-methylbut-3-yn-2- ol k) PHT-427 or 4-dodecyl-N-(l,3,4-thiadiazol-2-yl)benzenesulfonamide
1) Trieiribine or Tricyclic nucleoside or Pentaazacentopthylene or 2-{5- amino-7-methyl-2,6,7,9,l l-pentaazatricycl.o[6.3.1.0A{4,12}]dodeca- 1(1 l),3,5,8(12),9-pentaen-2-yl}-5-(hydroxymethyl)oxolane-3,4-diol m) AZD5363 or 4-amino-N-[(lS)-l-(4-chlorophenyl)-3-hydroxypropyl]-l- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide n) Deguelin or 522-17-8 or (-)-cis-deguelin or (-)-Deguelin or Munduleasericea or (lS,l4S)-l7,l8-dimethoxy-7,7-dimethyl-2,8,21 - trioxapentacyclo[12.8.0.0A{3,12} .0A{4,9} .0A{ 15,20}]docosa- 3(12),4(9),5 ,10,15 (20), 16, 8-heptaen- 13-one o) Nelfinavir OR Viracepl (TN) OR VRX496 OR Nelfinavir Monometharie Sulfonate OR (3S,4aS,8aS)-N-tert-butyl-2-[(2R,3 )-2-hydroxy-3-[(3- hydroxy-2-met ylbenzoyl)amino]-4-phenylsulfanylbutyl]- 3,4,4a,5,6,7,8,8a-octahydro-lH-isoquinoline-3-carboxamide
p) Amprenavir OR Agenerase OR Prozei OR Vertex OR 161814-49-9 OR VX-478 OR Vertex VX478 OR 141 W94 OR VX 478 OR [(3S)-oxolan-3- yl] N-[(2S,3R)-4-[(4-aminophenyl)sulfonyl-(2-methylpropyl)amino]-3- hydroxy- 1 -phenylbutan-2-yl]carbamate
q) Tipranavir OR Aptivus OR PNU-I 40690 OR 174484-41-4 OR Aptivus(TM) OR Tipranavir (INN) OR Aptivus (TN) OR Aptivus (Boehringer Ingelheim) OR TPV OR N-[3-[(lR)-l-[(2R)-4-hydroxy-6- oxo-2-(2-phenylethyl)-2-propyl-3H-pyran-5-yl]propyl]phenyl]-5- (trifluoromethy 1 )pyri di ne-2 - sulfon amide
r) Indinavir OR Compoimd J OR Crixivan OR (2S)-l-[(2S,4R)^-benzyl-2- hydroxy-5-[[( 1 S,2R)-2-hydroxy-2,3-dihydro- lH-inden- 1 -yl]amino]-5- oxopentyl]-N-tert-butyl-4-(pyridin-3-ylmethyl)piperazine-2-carboxamide s) Saquinavir OR saquinavir OR Fortovase OR 127779-20-8 OR Ro-31 -8959 OR lhxb OR 2fgu OR 2fgv OR Fortovase(TM) OR Fortovase (TN) OR (2S)-N-[(2S,3R)-4-[(3S,4aS,8aS)-3-(tert-butylcarbamoyl)- 3,4,4a,5,6,7,8,8a-octahydro-lH-isoquinolin-2-yl]-3-hydroxy-l- phenylbutan-2-yl]-2-(quinoline-2-carbonylamino)butanediamide t) Lopinavir OR Aluviran OR ABT-378 OR Koletra OR ABT 378 OR (2S)- N- [(2 S ,4S ,5 S)-5 - [ [2-(2 ,6-dimethylphenoxy)acetyl] amino] -4-hydroxy- 1,6- diphenylhexan-2-yl]-3-methyl-2-(2-oxo- 1 ,3-diazinan- 1 -yl)butan amide u) Fosamprenavir OR Telzir OR Fosamprenavir [INN] OR GW433908 OR Teizir(TM) OR VX 175 OR Amprenavir phosphate OR Lexiva (TM) OR Fosamprenavir (INN) OR [(3S)-oxolan-3-yl] N-[(2S,3R)-4-[(4- aminophenyl)sulfonyl-(2-methylpropyl)amino]-l-phenyl-3- phosphonooxybutan-2-yl]carbamate
v) Ritonavir OR Norvir OR Norvir Sec OR Abbott 84538 OR 155213-67-5 OR ABT-538 OR A-84538 OR I hxw OR Ritonavir [USAN] OR Norvir (TM) OR l,3-thiazol-5-ylmethyl N-[(2S,3S,5S)-3-hydroxy-5-[[(2S)-3- methyl-2-[[methyl-[(2-propan-2-yl - 1 ,3-thiazol-4- yl)methyl]carbamoyl]amino]butanoyl]amino]-l,6-diphenylhexan-2- yljcarbamate
w) Darunavir OR Prezista OR TMC-114 OR TMC114 OR UIC-94017 OR Darunavirum OR TMC 114 OR [(3aS,4R,6aR)-2,3,3a,4,5,6a- hexahydrofuro[2,3-b]fiiran-4-yl] N-[(2S,3R)-4-[(4-aminophenyl)sulfonyl- (2-methylpropyi)amino]-3~hydroxy-l~phenylbutan~2-yl]earbarnate x) Atazanavir OR Laiazanavir OR Zrivada OR Reyataz OR BMS-232632 OR methyl N-[(2S)-l-[2-[(2S,3S)-2-hydroxy-3-[[(2S)-2- (methoxycarbonylamino)-3,3-dimethylbutanoyl]amino]-4-phenylbutyl]-2- [(4-pyridin-2-ylphenylJmethyl]hydrazinyl]-3,3-dimethyl-l-oxobutan-2- yljcarbamate
y) Brecanavir OR GW64085X OR GW0385 OR GW640385 OR [(3aS,4R,6aR)~2 ,3a,4,5,6a-hexahydrofiiiO[2,3~b]furan-4-yl] N-[(2S,3R)- 4-[ 1 ,3 -benzodiox ol-5-yl sulfonyl(2 -methyl propyl)am ino] -3 -hydroxy- 1 - [4- [(2-methyl-l,3-thiazol-4-yl)methoxy]phenyl]butan-2-yl]carbamate.
Non-limiting examples of CW 168 include:
a) Celecoxib or Celebrex or Celebra or Celocoxib or Celecox or Onsenal or Xilebao or SC 58635 or 4-[5-(4-methylphenyl)-3-(trifluoromethyl)pyrazol-l- yljbenzenesulfonamide. b) Acemetacin or Rantudil or Emflex or 53164-05-9 or Acemetacinum or Aximeixin or Rheumibis or Acemix or 2-[2-[l -(4-chlorobenzoyl)-5-methoxy- 2-methylindol-3-yl]acetyl]oxyacetic acid. c) Acetaminophen or Paracetamol or 4-Acetamidophenol or Tylenol or APAP or Datril or Acetaminofen or Algotropyl or Naprinol or Lonarid or N-(4- hydroxyp henyl)acetam ide , d) Aspirin or ACETYLSALICYLIC ACID or 2-Acetoxybenzoic acid or Acylpyrin or Ecotrin or Acenterine or Polopiryna or Acetosal or Colfarit or Enterosarein or 2-acetyloxybenzoic acid. e) Diclofenac or Diclofenac acid or dichlofenac or Novapirina or Pennsaid or Voltaren or Voltarol or ProSorb-D or Diclofenacum or 2-[2-(2,6- dichloroanilino)phenyl] acetic acid. f) DuP-697 or 5-bromo-2-(4-iluorophenyl)-3-(4-methylsulfonylphenyl)thiophene g) Etodolac or Etodolic acid or Ultradol or Lodine or 2-(l,8-diethyl-4,9-dihydro- 3H-pyrano[3,4-b]indol-l-yl)acetic acid.
h) Etodolac acid or ultradol, lodine, 2-(l,8- diethyl-4,9-dihydro-3H-pyranol[3, 4- b]indol-l-yl) acetic acid. i) FK-331 1 or N-[4-acetyl-2-(2,4-difluorophenoxy)phenyl]methanesulfonamide.
Flufenamic Acid or Achless or Fluphenamic acid or Flufacid or Fullsafe Lanceat or Nichisedan or Paraflu or Plostene or 2- (trifluoromethyl)anilino]benzoic acid. k) Flurbiprofen or Ansaid or Froben or Cebutid or Ocufen or Flugalin or Flurofen or Antadys or Novo-Flurprofen or Nu-Flurbiprofen or 2-(3-fluoro-4- phenylphenyl)propanoic acid.
1) FR-122047 or [4,5-bis(4-methoxyphenyl)-l,3-thiazol-2-yl]-(4- methylpiperazin- 1 -yl)methanone. m) Ibuprofen or Brufen or Motrin or Dolgit or Liptan or Nuprin or Anflagen or Buburone or Butylenin or Ibumetin or 2-[4-(2-methylpropyl)phenyl]propanoic acid. n) Indomethacin or indorneiacin or Meiindol or Imbrilon or Indocid or Indocin or Tannex or Amuno or Indomethacine or Indomethacinum or 2-[l-(4- chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetic acid. o) Ketoprofen or Profenid or Orudis or Alrheumat or Alrheurnun or Capisien or Oruvail or Actron or Epatec or 2-(3-benzoylphenyl)propanoic acid. p) Ketorolac or Macril or 5-benzoyl-2,3-dihydro-l H-pyrroli.zine-l-carboxylic acid.
q) Naproxen or Naproxene or Calosen or Axer or d -Naproxen or Aleve or Acusprain or (2S)-2-(6-methoxynaphthalen-2-yl)propanoic acid.
Nifluniic Acid or Niflurii or Landruma or Forenol or Actol or Donalgin Niflumate or Niflam or Nifluminic acid or 2- (trifluoromethyl)anilino]pyridine-3-carboxylic acid. s) Nimesulide or Mesulid or Nimed or Aniifloxil or Flogovital or Sulidene or Guaxan or N-(4-nitro-2-phenoxyphenyl)methanesul.fonamide. t) NS-398 or ns-398 or NS 398 or N-[2-(Cyclohexyloxy)-4- nitrophenyljmethanesulfbnamide or NS398 or 123653-11-2 or N-(2- cyclohexyloxy-4-nitrophenyl.)methanesulfonamide. u) Piroxicam or Feldene or Roxicam or BAXO or Pyroxvcarn or Piroxicamum or Artroxicam or Bruxicam or Caliment or 4-hydroxy-2-methyl-l,l-dioxo-N- pyridin-2-yl-^6,2-benzothiazine-3-carboxamide. v) Resveratrol or Resvida or 5-[(E)-2-(4-hydroxyphenyl)ethenyl]benzene-l,3- diol. w) Rofecoxib or Vioxx or Ceoxx or MK 966 or MK 0966 or 3-(4- methylsulfonylphenyl)-4-phenyl-2H-furan-5-one. x) SC-560 or 5-(4-chlorophenyl)-l-(4-methoxyphenyl)-3-
(trifluoromelhyi)pyrazole. y) SC-58125 or 5-(4-fluorophenyl)-l-(4-methylsulfonylphenyl)-3-
(trifluoromethyl ) pyrazole . z) Sulindac or Clinoril or Arthrocine or Sulindacsulfoxide or Arthrobid or Klinoril or Mobilin or 2-[(3Z)-6-fluoro-2-methyl-3-[(4- methyl.sulfinyl.phenyl.)methylidene]inden-l -yl]acetic acid, aa) Talnitiumate or Lornucin or Somalgen or (3-oxo-lH-2-benzofuran-l-yl) 2-[3-
(trifluoromethyl)anilino]pyridine-3-carboxylate.
bb) Tenidap or (3Z)-5-chloro-3-[hydroxy(thiophen-2-yl)methylidene]-2- oxoindole- 1 -carboxamide. cc) Valdecoxib or Bextra or Valdyn or Kudeq or 4-(5-methyl-3-phenyl-l,2-oxazol- 4-yl)benzenesulfonamide.
Non-limiting examples of CW254 include:
a) Zileuion or Zyflo or Leuirol or Zyflo CR or Zileutonum or 111406-87-2 or Ziluton or Abbott 64077 or CHEBI: 1()112 or l -[l-(l-benzothiophen-2- yl)ethyl] - 1 -hydroxyurea . b) Bayx-1005 or Veliflapon or Bay X 1005 or Bayx-1005 or Bay X1005 or DG- 031 or Bay-X1005 or Veliflapon (USAN/INN) or AC1L3X6M or Bay-x-1005 or CHEMBL88712 or (2R)-2-cyclopentyl-2-[4-(quinolin-2- ylmeihoxy)phenyl]acetic acid. c) BW B70C or l-[(E)-4-[3-(4-fluorophenoxy)phenyl]but-3-en-2-yl]-l- hydroxyurea. d) MK886 or L 663536 or 3-[3-tert-butylsulfanyl-l -[(4-chlorophenyl)methyl]-5- propan-2-ylindol-2-yl]-2,2-dimethylpropanoic acid. e) PD 146176 or 6,11 -dihydrothiochromeno[4,3-b]indole. f) STEARDA or T5678727 or N-stearoyl-dopamine or N-[2-(3,4- dihydroxyphenyl)ethy 1 ] octadecanamide . g) 2-TEDC or 2-(l -Thienyl)ethyl 3,4-dihydroxybenzylidenecyanoacetate.
Non-limiting examples of CW145 include the compounds of Table 1A.
Table lA: CW145 Compound Names and Chemical Structures (Direct inhibitors
Figure imgf000053_0001
Figure imgf000054_0002
Figure imgf000054_0001
4- [2-(4-amino-l,2, :
oxadiazol-3 -yl - 1 -ethyl -
7-[[(3S)-piperidin-3-
GSK690693
yl]methoxy]irmdazo[4,
5- c]pyridin-4-yl]-2- methylbut-3 -yn-2-ol
8-[4-(l- aminocyclobutyl)phenyl] -9-phenyl-2H-
MK2206
[l ,2,4]triazolo[3,4- i] [ 1 ,6]naphthyridin-3- on e; dihydro chloride
(1,1 -dimethylpiperidin-
KRX-0401, NSC
PE IFOSINE l-ium-4-yl) octadecyl
639966, D 21266
phosphate
4-dodecyl-N-( 1 ,3,4-
PHT-427 thiadiazol-2- yl)benzenesulfonamide
2-{5-amino-7-methyl- 2,6,7,9,11- pentaazatricyclo [6.3.1.0A
Tricyclic nucleoside,
{4,12}]dodeca-
Triciribine Pentaazacentopthyle
1(11),3,5,8(12),9- ne
pentaen-2-yl}-5-
(hydroxymethyl)oxolane
-3,4-diol
4-amino-N-[(lS)-l-(4- chlorophenyl)-3 - hydroxypropyl]- 1 -(7H-
AZD5363
pyrrolo [2 , 3 -djpyrimidin- 4-yl)piperidine-4- carboxamide
(1S,14S)-17,18- dimeth oxy-7 , 7-di m ethyl -
522-17-8, (-)-cis- 2,8,21- deguelin, (-)- triox apen tacy clo [12,8.0.
Deguelin
Deguelin, 0Λ{3,12}.0Α{4,9}.0Α{15,
M unduleasericea 20}]docosa- 3(12),4(9),5, 10,15(20),! Xx. 6, 18-heptaen- 13 -one
Table IB: CW145 Compound Names and Chemical Structures (Indirect inhibitors of AKT)
Figure imgf000057_0001
Aptivus, PNU-
N-[3-[(l R)-l-[(2R)-4-
140690, 174484- hydroxy-6-oxo-2-(2- 41-4, Aptivus(TM),
phenylethyl)-2-propyl- Tipranavir (INN),
Tipranavir 3H-pyran-5- Aptivus (TN),
yl]propyl]phenyl]-5- Aptivus
(trifluoromethyl)pyridin
(Boehringer
e~2 -sulfonamide
Ingelheim), TPV
(2S)-l -[(2S,4R)-4- benzyl-2-hydroxy-5-
[[(l S,2R)-2-hydroxy-
2,3-dihydro- 1 H-inden-
Compound ¾¾s
Indinavir l-yl]amino]-5-
..nxjvan
oxopentyi] -N-tert-butyl-
4-(pyridin-3- ylmethyl.)piperazine-2- carboxamide
(2S)-N-[(2S,3R)-4-
[(3S,4aS,8aS)-3-(tert- sagumavir, butylcarbamoyl)- Fortovase, 127779- 3,4,4a,5,6,7,8,8a- 20-8, Ro-31-8959, octahydro-lH-
Saquinavir
lhxb, 2fgu, 2fgv, isoquinolin-2-yl] -3 - Fortovase (TM), hydroxy- 1 -phenylbutan- Fortovase (TN) 2-yl]-2-(quinoline-2- earbonylamino butanedi
amide (2S)-N-[(2S,4S,5S)-5- [[2-(2,6- dimethylphenoxy)acetyl
Aluviran, ABT-378, ] amino] - -hydroxy- 1 ,6-
Lopinavir
Koletra, ABT 378 diphenylhexan-2-yl] -3 - methyl-2-(2 -oxo-1 ,3- diazinan-1- yl)butanamide
Telzir,
-oxolan-3-yl] N-
Fosamprenavir
[(2S,3R)-4-[(4- [INN], GW433908,
aminophenyl)sulfonyl- Telzir(TM), VX
(2-
Fosamprenavir 175, Amprenavir
methylpropyl)amino] - 1 - phosphate, Lexiva
phenyl-3- ( C S.
phosphonooxybutan-2-
Fosamprenavir
yl] carbamate
1 ,3 -thiazol-5 -ylmethyl
N-[(2S,3S,5S)-3-
Norvir, Norvir Sec,
hydroxy-5-[[(2S)-3- Abbott 84538,
methyl-2-[[methyl-[(2- 155213-67-5, ABT- propan-2-yl-l ,3-thiazol-
Ritonavir 538, A-84538,
4- Ihxw, Ritonavir
yl)methyl] carbamoyl] a [USAN], Norvir
mino]butanoyl] amino] - (TM)
1 ,6-diphenylhexan-2- yl] carbamate
Figure imgf000060_0001
yl)methoxy]phenyl]buta
Figure imgf000061_0001
Non-limiting examples of CW168 include the compounds of Table 2.
Table 2: CW168 Compound Name mad Chemical Structure.
Figure imgf000061_0002
ACETYLSALICYLI
C ACID, 2- Acetoxybenzoic
acid, Acylpyrin,
Aspirin -acetvloxvbenzoic acid
Ecotrin, Acenterine,
Polopiryna,
Acetosal, Colfarit,
Enterosarein
Celebrex, G
4-[5-(4-methylphenyl)-3-
Celocoxib, Celecox,
Celecoxib (trifluoromethyl)pyrazol-
Onsenal, Xilebao,
1 -yljbenzenesulfonamide SC 58635
Diclofenac acid,
dichlofenac,
2-[2-(2,6- Novapirina,
Diclofenac dichloroanilino)phenyl]ac
Pennsaid, Voltaren,
etic acid
Voltarol, ProSorb-D,
Diclofenacum
5-bromo-2-(4-
ΙΙϊΙΗΙΙίΙΙ II fluorophenyl)-3 -(4-
DuP-697
methylsulfonylphenyl)thi
ophene
2-(l,8-diethyl-4,9-
Etodolic acid,
Etodolac dihydro-3 H-pyrano [3 ,4- i liiliilll
Ultradol, Lodine
bjjindol- 1 -vljacetic acid
N-[4-acetyl-2-(2,4-
F -3311 difluorophenoxy)phenyl]
methanesulfonamide X)
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
3-(4-
Vioxx, Ceoxx,MK
Rofecoxib methy 1 sulfonylphenyl) -4-
966, MK 0966
phenyl-2H-furan-5-one
5-(4-chlorophenyl)-l-(4-
SC-560 methoxyphenyl)-3 - (trifluoromethyl)pyrazole
5 ~( -fluorophenyl)- 1 -(4- methy 1 sulfonylphenyl) -3 -
SC-58125
(trifluoromethyl) pyrazole
Figure imgf000069_0001
4-(5 -methyl-3 -phenyl-
B extra, Valdyn,
Valdecoxib l ,2-oxazol-4- udeq
yljbenzenesulfonamide
2-[2-(4-chlorophenyl)- 6,6-dimethyl - 1 -phenyl-5 ,
Licofelone ML-3000
7-dihydropyrrolizin-3 - yl] acetic acid
Figure imgf000070_0001
Non-limiting examples of CW254 include the compounds of Table 3.
Table 3: CW254 Compound Names and Chemical Structures,
Figure imgf000070_0002
Figure imgf000071_0001
Figure imgf000072_0001
In an embodiment, the disclosure provides the use of pharmaceutically-acceptable salts of any compound described herein. Pharmaceutically-acceptable salts include, for example, acid-addition salts and base-addition salts. The acid that is added to the compound to form an acid-addition salt can be an organic acid or an inorganic acid. A base that is added to the compound to form a base-addition salt can be an organic base or an inorganic base. In an embodiment, a pharmaceutically-acceptable salt is a metal salt. In an embodiment, a pharmaceutically-acceptable salt is an ammonium salt. Metal salts arise from the addition of an inorganic base to a compound of the disclosure, The inorganic base consists of a metal cation paired with a basic counterion, such as, for example, hydroxide, carbonate, bicarbonate, or phosphate. The metal can be an alkali metal, alkaline earth metal, transition metal, or main group metal. In anembodiment, the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium or zinc.
In an embodiment of the present disclosure, a metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt or a zinc salt. Ammonium salts can arise from the addition of ammonia or an organic amine to a compound of the disclosure. In an embodiment, the organic amine is triethyl amine, diisopropyl amine, ethanol amine, diethanol amine, Methanol amine, morpholine, N-methylmorpholine, piperidine, N- methylpiperidine, N-ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrrazole, pipyrrazole, imidazole, pyrazine, or pipyrazine.
In an embodiment of the present disclosure, an ammonium salt is a triethyl amine salt, a diisopropyl amine salt, an ethanol amine salt, a diethanol amine salt, a Methanol amine salt, a morpholine salt, an -methylmo holine salt, a piperidine salt, an N- methylpiperidine salt, an N-ethylpiperidine salt, a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrrazole salt, a pipyrrazole salt, an imidazole salt, a pyrazine salt, or a pipyrazine salt.
Acid addition salts can arise from the addition of an acid to a compound of the disclosure. In an embodiment, the acid is organic. In another embodiment, the acid is inorganic. In an embodiment, the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, a phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisinic acid, gluconic acid, glucaronic acid, saccaric acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, citric acid, oxalic acid or maleic acid. In an embodiment of the present disclosure, the salt is a hydrochloride salt, a hydrobromi.de salt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfate salt, a sulfite salt, a phosphate salt, isonicotinate salt, a lactate salt, a salicylate salt, a tartrate salt, an ascorbate salt, a gentisinate salt, a gluconate salt, a glucaronate salt, a saccarate salt, a formate salt, a benzoate salt, a glutamate salt, a pantothenate salt, an acetate salt, a propionate salt, a butyrate salt, a fumarate salt, a succinate salt, a methanesulfonate (mesylate) salt, an etlianesulfonate salt, a benzenesulfonate salt, a p- toluenesulfonate salt, a citrate salt, an oxalate salt , or a maleate salt.
In an embodiment of the present disclosure, excipients are selected from a group comprising granulating agents, binding agents, lubricating agents, disintegrating agents, sweetening agents, glidants, anti-adherents, anti-static agents, surfactants, antioxidants, gums, coating agents, coloring agents, flavouring agents, coating agents, plasticizers, preservatives, suspending agents, emulsifying agents, plant cellulosic material, spheroni.zati.on agents and any combination thereof.
Pharmaceutical Compositions
The present disclosure further relates to a process for obtaining a composition of CW145and atleast one of the compounds selected from a group comprising CW.168 and CW254, optionally along with pharmaceutically acceptable excipient(s), said process comprising act of combining said compounds in any order thereof.
In an embodiment of the present disclosure, the pharmaceutical composition of the disclosure is a combination of any pharmaceutical compounds described herein with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. Pharmaceutical compositions are administered in therapeutically-effective amounts as pharmaceutical compositions by any form and route known in the art including, for example, intravenous, subcutaneous, intramuscular, oral, rectal, aerosol, parenteral, ophthalmic, pulmonary, transdermal, vaginal, otic, nasal, and topical administration. In an embodiment of the present disclosure, the pharmaceutical composition is administered in a local or systemic manner, for example, through injection of the compound directly into an organ, optionally in a depot or sustained release formulation. Pharmaceutical compositions are provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation. A rapid release form provides an immediate release. An extended release formulation provides a controlled release or a sustained delayed release. In an embodiment of the present disclosure, pharmaceutical compositions for oral administration is formulated readily by combining the active compounds with pharmaceutically acceptable carriers or excipients well known in the art. Such carriers can be used to formulate tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like, for oral ingestion by a subject.
In an embodiment of the present disclosure, pharmaceutical preparations for oral use is obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Cores can be provided with suitable coatings. For this purpose, concentrated sugar solutions can be used, which may optionally contain an excipient such as gum arable, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments are added to the tablets or dragee coatings, for example, for identification or to characterize different combinations of active compound doses.
In an embodimeni of the present disclosure, pharmaceutical preparations which are used orally include push-fit capsules made of gelatin, as well as soil, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In an embodiment, the capsule comprises a hard gelatin capsule comprising one or more of pharmaceutical, bovine, and plant gelatins. A gelatin may be alkaline processed. The push-fit capsules contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols, Stabilizers may be added. All formulations for oral administration are provided in dosages suitable for such administration.
In an embodiment of the present disclosure, the compositions are tablets, lozenges, or gels, forbuccal or sublingual administration.
In an embodiment of the present disclosure, parental injections are formulated for bolus injection or continuous infusion. The pharmaceutical compositions are in a form suitable for parenteral injection as a sterile suspension, solution or emulsion in oily or aqueous vehicles, and contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Suspensions of the active compounds can be prepared as oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. The suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen- free water, before use. In an embodiment of the present disclosure, the active compounds are administered topically and are formulated into a variety of topically administrate compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, and ointments, Such pharmaceutical compositions may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
In an embodiment of the present disclosure, formulations suitable for transdermal administration of the active compounds may employ transdermal delivery devices and transdermal delivery patches, and may be lipophilic emulsions or buffered aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical compounds. Transdermal delivery may be accomplished by means of iontophoretic patches and the like. Additionally, transdermal patches provide controlled delivery. The rate of absorption is slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel . Conversely, absorption enhancers may be used to increase absorption. An absorption enhancer or carrier may include absorbable pharmaceutically acceptable solvents to assist passage through the skin. For example, transdermal devices can be in the form of a bandage comprising a backing member, a reservoir containing compounds and carriers, a rate controlling barrier to deliver the compounds to the skin of the subject at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
In an embodiment of the present disclosure, the active compounds for administration by inhalation are in a form as an aerosol, a mist, or a powder. Pharmaceutical compositions are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, diehlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit is determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator is formulated containing a powder mix of the compounds and a suitable powder base such as lactose or starch. In an embodiment of the present disclosure, the compounds are fonnulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. In suppository forms of the compositions, a low-melting wax such as a mixture of fatty acid glycerides, optionally in combination with cocoa butter, is first melted.
In practicing the methods of treatment or use provided herein, therapeutically- effective amounts of the compounds described herein are administered in pharmaceutical compositions to a subject having a disease or condition to be treated. In an embodiment, the subject is a mammal such as a human, A therapeutically- effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compounds used and other factors. The compounds are used singly or in combination with one or more therapeutic agents as components of mixtures.
In an embodiment of the present disclosure, pharmaceutical compositions are formulated using one or more physiologically-acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations that can be used pharmaceutically. Formulation is modified depending upon the route of administration chosen. Pharmaceutical compositions comprising compounds described herein are manufactured in a conventional manner, for example, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
In an embodiment of the present disclosure, the pharmaceutical compositions include at least one pharmaceutically acceptable carrier, diluent, or excipient and compounds described herein as free-base or pharmaceutically-acceptable salt form. The methods and pharmaceutical compositions described herein include the use of crystalline forms (also known as polymorphs), and active metabolites of these compounds having the same type of activity.
In an embodiment of the present disclosure, methods for the preparation of compositions comprising the compounds described herein include formulating the compounds with one or more inert, pharmaceutically-acceptable excipients or carriers to form a solid, semi-solid, or liquid composition. Solid compositions include, for example, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include, for example, solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. Semi-solid compositions include, for example, gels, suspensions and creams. The compositions can be in liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions may also contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives. In an embodiment of the present disclosure, composition comprising compounds can be delivered via liposomal technology. The use of liposomes as drug earners increases the therapeutic index of the compounds. Liposomes are composed of natural phospholipids, and contain mixed lipid chains with surfactant properties (e.g., egg phosphatidyl eihanolamine). A liposome design employs surface ligands for attaching to unhealthy tissue. Non-limiting examples of liposomes include the multilamellar vesicle (MLV), the small unilamellarvesicle (SUV), and the large unilamellar vesicle (LUV). Liposomal physicochemical properties are modulated to optimize penetration through biological barriers and retention at the site of administration, and to prevent premature degradation and toxicity to non-target tissues. Optimal liposomal properties depend on the administration route: large-sized liposomes show good retention upon local injection, small-sized liposomes are better suited to achieve passive targeting. PEGylation reduces the uptake of the liposomes by liver and spleen, and increases the circulation time, resulting in increased localization at the inflamed site due to the enhanced permeability and retention (EPR) effect. Additionally, liposomal surfaces are modified to achieve selective delivery of the encapsulated drug to specific target cells. Non-limiting examples of targeting ligands include monoclonal antibodies, vitamins, peptides, and polysaccharides specific for receptors concentrated on the surface of cells associated with the disease. In an embodiment of the present disclosure, compounds are delivered through antibody-drug conjugates (ADCs) technology. Here, drugs are conjugated/fused to tumor-specific antibodies so as to deliver the drug to the site of tumor and increase their therapeutic efficacy. ADCs have been developed for targeted delivery of anticancer drugs to tumor in the patient body with the aim of bypassing the morbidity common to conventional drug delivery.
In an embodiment of the present disclosure, non-limiting examples of dosage forms suitable for use in the disclosure include feed, food, pellet, lozenge, liquid, elixir, aerosol, inhalant, spray, powder, tablet, pill, capsule, gel, geltab, nanosuspension, nanoparticle, microgel, suppository troches, aqueous or oily suspensions, ointment, patch, lotion, dentifrice, emulsion, creams, drops, dispersible powders or granules, emulsion in hard or soft gel capsules, syrups, phytoceuticals, nutraceuticals and any combination thereof.
In an embodiment of the present disclosure, non-limiting examples of pharmaceutically-acceptable excipients suitable for use in the disclosure include granulating agents, binding agents, lubricating agents, disintegrating agents, sweetening agents, glidants, anti-adherents, anti-static agents, surfactants, anti- oxidants, gums, coating agents, coloring agents, flavouring agents, coating agents, plasticizers, preservatives, suspending agents, emulsifying agents, plant cellulosic material and spheronization agents, and any combination thereof.
In an embodiment of the present disclosure, a composition of the disclosure is, for example, an immediate release form or a controlled release formulation. An immediate release formulation is formulated to allow the compounds to act rapidly. Non-limiting examples of immediate release formulations include readily dissolvable formulations. A controlled release formulation is a pharmaceutical formulation that has been adapted such that drug release rates and drag release profiles can be matched to physiological and chronotherapeutic requirements or, alternatively, has been formulated to effect release of a drug at a programmed rate. Non-limiting examples of controlled release formulations include granules, delayed release granules, hydrogels (e.g., of synthetic or natural origin), other gelling agents (e.g., gel-forming dietary fibers), matrix -based formulations (e.g., formulations comprising a polymeric material having at least one active ingredient dispersed through), granules within a matrix, polymeric mixtures, granular masses, and the like.
In an embodiment of the present disclosure, compositions of the disclosure are delivered through a time-controlled delivery system. An example of a suitable time- controlled delivery system is the PULSINCAP® system, or a variant thereof. The time-controlled delivery system may further comprise pH-dependent systems, microbially-triggered delivery systems, or a combination thereof. The time-controlled system may comprise a water insoluble capsule body enclosing a drug reservoir. The capsule body may be closed at one end with a hydrogel plug. The hydrogel plug can comprise swellable polymers, erodible compressed polymers, congealed melted polymers, enzymatically-controUed erodible polymers, or a combination thereof, The swellable polymers include polymethacrylates. Non-limiting examples of erodible compressed polymers include hydroxypropyl methylcellulose, polyvinyl alcohol, polyvinyl acetate, polyethylene oxide, and combinations thereof. Non-limiting examples of congealed melted polymers include saturated polyglycolated glycerides, glycerylmonooleate, and combinations thereof. Non-limiting examples of enzymatically-controUed erodible polymers include polysaccharides; amylose; guar gum; pectin; chitosan; inulin; cyclodextrin; chondroitin sulphate; dextrans; locust bean gum; arabinogalactan; chondroitin sulfate; xylan; calcium pectinate; pectin/chitosan mixtures; amidated pectin; and combinations thereof.
In an embodiment of the present disclosure, the time-controlled delivery system comprise a capsule, which farther comprises an organic acid. The organic acid may be filled into the body of a hard gelatine capsule. The capsule may be coated with multiple layers of polymers. The capsule may be coated first with an acid soluble polymer, such as EUDRAGIT'8' E, then with a hydrophilic polymer, such as hydroxypropyl methylcellulose, and finally with an enteric coating, such as EUDRAGIT® L.
In an embodiment of the present disclosure, an additional example of a suitable time- controlled delivery system is the CHRONOTROPIC* system, or a variant thereof, which comprises a drag core that is coated with hydroxypropyl methylcellulose and an outer enteric film.
In an embodiment of the present disclosure, an additional example of a suitable time- controlled delivery system is the CODES iM system, or a variant thereof. The time- controlled delivery system comprise a capsule body, which can house, for example, a drug-containing tablet, an erodible tablet, a swelling expulsion excipient, or any combination thereof. The capsule may comprise an ethyl cellulose coat. The time- controlled delivery system may comprise two different sized capsules, one inside the other. The space between the capsules may comprise a hydrophilic polymer. The drug-containing core can be housed within the inner capsule. The drug delivery system comprise an impermeable shell, a drag-containing core, and erodibie outer layers at each open end, When the outer layers erode, the drug is released.
In an embodiment of the present disclosure, examples of suitable multiparticulate drag delivery systems include DIFFUCAPS®, DIFFUTAB®, ORB EX A®, Eli RA !) MINITABS®, MICROCAPS® and variants thereof. The drug delivery system comprise multiparticulate beads, which are comprised of multiple layers of the drug compound, excipients, and release-controlling polymers. The multiparticulate beads comprise an organic acid or alkaline buffer. The multiparticulate beads comprise a solid solution of the drug compound and crystallization inhibitor. The drug delivery system comprise a matrix tablet containing water-soluble particles and the drug compound. The matrix tablet may further comprise hydrophiiic and hydrophobic polymers. In some multiparticulate delivery systems, particles in the micron size range are used. In some multiparticulate delivery systems, nanoparticle colloidal carriers composed of natural or synthetic polymers are used.
In an embodiment of the present disclosure, a controlled release formulation is a delayed release form. A delayed release form is formulated to delay a compound's action for an extended period of time. A delayed release form is formulated to delay the release of an effective dose of one or more compounds, for example, for about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, or about 24 hours. In an embodiment of the present disclosure, a controlled release formulation is a sustained release form. A sustained release form is formulated to sustain, for example, the compound's action over an extended period of time. A sustained release form is formulated to provide an effective dose of any compound described herein (e.g., provide a physiologically-effective blood profile) over about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21 , about 22, about 23, or about 24 hours. In an embodiment of the present disclosure, a tablet providing a sustained or controlled release comprise a first layer containing one or two of the compounds described herein, and a tablet core containing one or two other compounds. The core can have a delayed or sustained dissolution rate. Other exemplary embodiments include a barrier between the first layer and core, to limit drag release from the surface of the core. Barriers can prevent dissolution of the core when the pharmaceutical formulation is first exposed to gastric fluid. For example, a barrier comprise a disintegrant, a dissolution-retarding coating (e.g., a polymeric material, for example, an enteric polymer such as a Eudragit polymer), or a hydrophobic coating or film, and may be selectively soluble in either the stomach or intestinal fluids. Such barriers permit the compounds to leach out slowly. The barriers can cover substantially the whole surface of the core.
In an embodiment of the present disclosure, non-limiting examples of pharmaceutically-acceptable excipients can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995): Hoover, John E., Remington 's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkinsl999), each of which is incorporated by reference in its entirety.
Posing
In an embodiment of the present disclosure, pharmaceutical compositions described herein are in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compounds. The unit dosage is in the form of a package containing discrete quantities of the formulation. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions are packaged in single-dose non-reclosable containers. Multiple-dose reclosable containers may be used, for example, in combination with a preservative. Formulations for parenteral injection are presented in unit dosage form, for example, in ampoules, or in multi-dose containers with a preservative. In an embodiment of the present disclosure, the compound described herein is present in a composition at a range of about 1 mg to about 3000 mg; from about 5 mg to about 1000 mg, from about 10 mg to about 500 mg, from about 50 mg to about 250 mg, from about 100 mg to about 200 mg, from about 1 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 150 mg, from about 150 mg to about 200 mg, from about 200 mg to about 250 mg, from about 250 mg to about 300 mg, from about 300 mg to about 350 mg, from about 350 mg to about 400 mg, from about 400 mg to about 450 mg, from about 450 mg to about 500 mg, from about 500 mg to about 550 mg, from about 550 mg to about 600 mg, from about 600 mg to about 650 mg, from about 650 mg to about 700 mg, from about 700 mg to about 750 mg, from about 750 mg to about 800 mg, from about 800 mg to about 850 mg, from about 850 mg to about 900 mg, from about 900 mg to about 950 mg, or from about 950 mg to about 1000 mg. In an embodiment of the present disclosure, the compound described herein is present in a composition in an amount of about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, or about 2000 mg.
In an embodiment of the present disclosure, a dose is expressed in terms of an amount of the drug divided by the mass of the subject, for example, milligrams of drag per kilograms of subject body mass. In an embodiment of the present disclosure, the composition comprises from about 625mg/day to about 3000mg/day of CW145, from about 600mg/kg/day to about 2400mg/kg/day of CW254and from about 200mg/day to about 800mg/day of CW168. In an embodiment, CW145 is present in a composition in an amount ranging from about 250 mg/kg to about 2000 mg/kg, about 10 mg/kg to about 800 mg/kg, about 50 mg/kg to about 400 mg/kg, about 100 mg kg to about 300 mg/kg, or about 150 mg/kg to about 200 mg kg. In an embodiment, CW254or CW168 is present in a composition in an amount ranging from about 1 mg/kg to about 300 mg/kg, about 2 mg/kg to about 200 mg/kg, about 3 mg kg to about 100 mg/kg, about 5 mg/kg to about 75 mg/kg, about 10 mg/kg to about 50 mg kg or about 20 mg/kg to about 40 mg kg
In an embodiment of the present disclosure, the composition comprises from about 100 mg/day to about 800 mg/day of CW145, from about 20 mg/kg/day to about 25 mg/kg/day of CW254or from about 5mg/day to about 80mg/day of CW168.
In an embodiment, CW145 is present in a composition in an amount ranging from about 600mg/kg to about 3000 mg/kg, about 10 mg/kg to about 800 mg/kg, about 50 mg kg to about 400 mg/kg, about 100 mg/kg to about 300 mg/kg, or about 150 mg/kg to about 200 mg/kg. in some embodiments, CW254 (include range from 600 to 2400 mg/day) or CW168 (range from 200 - 800 mg/day) is present in a composition in an amount ranging from about 1 mg/kg to about 300 mg/kg, about 2 mg/kg to about 200 mg/kg, about 3 mg kg to about 100 mg/kg, about 5 mg/kg to about 75 mg/kg, about 10 mg/kg to about 50 mg kg or about 20 mg/kg to about 40 mg/'kg.
In an embodiment of the present disclosure, the composition comprises from about 600 mg/day to about 3000mg/day of CW 145, from about 600 mg/kg/day to 2400 mg/kg/day of CW254 or from about lOOmg/day to about 800mg/day of CW168.
In an embodiment of the present disclosure, the compound described herein is present in a composition in an amount that is a fraction or percentage of the maximum tolerated amount. The maximum tolerated amount is as determ ined in a subject, such as a mouse or human. The fraction is expressed as a ratio of the amount present in the composition divided by the maximum tolerated dose. The ratio is from about 1/20 to about 1/1. The ratio is about 1/20, about 1/19, about 1/18, about 1/17, about 1/16, about 1/15, about 1/14, about 1/13, about 1/12, about 1/11, about 1/10, about 1/9, about 1/8, about 1/7, about 1/6, about 1/5, about 1/4, about 1/3, about 1/2, or about 1/1. The ratio is 1/20, 1/19, 1/18, 1/17, 1/16, 1/15, 1 /14, 1/13, 1/12, 1/1 1 , 1/10, 1/9, 1/8, 1/7, 1/6, 1/5, 1/4, 1/3, 1/2, or 1/1. The ratio is in a range from about 5% to about 100%, from about 10% to about 100%, from about 5% to about 80%, from about 10% to about 80%, from about 5% to about 60%, from about 10% to about 60%, from about 5% to about 50%, from about 10% to about 50%, from about 5% to about 40%, from about 10% to about 40%, from about 5% to about 20%, or from about 10% to about 20%. The ratio is about 5%, about 10%, about 15%:·, about 20%>, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%).
The foregoing ranges are merely suggestive. Dosages are altered depending on a number of variables, including, for example, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
In an embodiment of the present disclosure, dose is modulated to achieve a desired pharmacokinetic or pharmacodynamics profile, such as a desired or effective blood profile, as described herein.
Pharmacokinetic and Pharmacodynamic Measurements
In an embodiment of the present disclosure, pharmacokinetic and pharmacodynamic data is obtained by techniques known in the art. Appropriate pharmacokinetic and pharmacodynamic profile components describing a particular composition may vary due to the inherent variation in pharmacokinetic and pharmacodynamic parameters of drug metabolism in human subjects. Pharmacokinetic and pharmacodynamic profiles are based on the determination of the mean parameters of a group of subjects. The group of subjects includes any reasonable number of subjects suitable for determining a representative mean, for example, 5 subjects, 1 0 subjects, 1 6 subjects, 20 subjects, 25 subjects, 30 subjects, 35 subjects, or more. The mean is determined by calculating the average of all subject's measurements for each parameter measured.
In an embodiment of the present disclosure, the pharmacokinet c parameters are any parameters suitable for describing a compound disclosed herein. For example, the Cmax may be not less than about 100 ng/mL; not less than about 200 ng/mL; not less than about 300 ng/mL; not less than about 400 ng/mL; not less than about 500 ng/mL; not less than about 600 ng/mL; not less than about 700 ng/mL; not less than about 800 ng/mL; not less than about 900 ng/mL; not less than about 1000 ng/mL; not less than about 1 250 ng/mL; not less than about 1 500 ng/mL; not less than about 1750 ng/mL; not less than about 2000 ng/mL; or any other Cmax appropriate for describing a pharmacokinetic profile of a compound described herein.
In an embodiment of the present disclosure, the Tma of a compound present in a composition described herein may be, for example, not greater than about 0.5 hours, not greater than about 1.0 hours, not greater than about 1.5 hours, not greater than about 2.0 hours, not greater than about 2.5 hours, not greater than about 3.0 hours, or any other Tinax appropriate for describing a pharmacokinetic profile of a compound described herein. In an embodiment of the present disclosure, the AU o-mf) of a compound present in a composition described herein may be, for example, not less than about 250 ng»hr/mL, not less than about 500 ng'hr/mL, not less than about 1000 ng»hr/mL, not less than about 1500 ng»hr/mL, not less than about 2000 ng»hr/mL, not less than about 3000 ng'hr/mL, not less than about 3500 ng ir/mL, not less than about 4000 ng»hr/mL, not less than about 5000 ng»hr/mL, not less than about 6000 ng»hr/mL, not less than about 7000 ngehr/mL, not less than about 8000 ng'hr/mL, not less than about 9000 ng»nr/mL, or any other AUC(o..ir.f) appropriate for describing a pharmacokinetic profile of a compound described herein. In an embodiment of the present disclosure, the plasma concentration of a compound present in the composition described herein about one hour after administration is, for example, not less than about 25 ng/niL, not less than about 50 ng/mL, not less than about 75 ng/mL, not less than about 100 ng/mL, not less than about 150 ng/mL, not less than about 200 ng/mL, not less than about 300 ng/mL, not less than about 400 ng/mL, not less than about 500 ng/mL, not less than about 600 ng/mL, not less than about 700 ng/mL, not less than about 800 ng/mL, not less than about 900 ng/mL, not less than about 1000 ng/mL, not less than about 1200 ng/mL, or any other plasma concentration of a compound described herein. In an embodiment of the present disclosure, the pharmacodynamic parameters are parameters suitable for describing compositions of the disclosure. For example, the pharmacodynamic profile may exhibit decreases in viability phenotype for the tumor cells or tumor size reduction in tumor cell lines or xenograft studies, for example, about 24 hours, about 48 hours, about 72 hours, or 1 week. The present disclosure further relates to a method for treating a subject either suspected of having or having condition or mutation or a combination thereof wherein said condition is selected from a group comprising, but not limiting to, cancers of the central nervous system such as glioblastoma multiforme, endometrial cancer, ovarian cancer, prostate cancer, breast cancer, pancreatic cancer, colorectal cancer, lung cancer, brain Cancer, head and neck cancer, multiple myeloma, acute non lymphocytic leukemia and myelodysplasia, or any combination of conditions thereof, or any condition having a mutation therein,
In an embodiment, the cancers wherein said mutation is in PTEN/PI3K/AKT genes alone or in combination with each other or in combination with mutation in other genes that promote cancer similar but not limited to BRAF, KRAS, EGFR, B-catenin, CD N2A, , APC, MYC, BCL2, SOCS1, SMAD4, TP53 etc or any combination of mutations thereof, said method comprising act of administering to the subject- composition of CW145 and atleast one of compound selected from a group comprising CW168 and CW254, or any combination thereof, optionally along with pharmaceutically acceptable excipient(s);
In an embodiment of the present disclosure, the compounds are administered as composition of C WHS and atleast one of compound selected from group comprising of CW168 and CW254, or any combination thereof, optionally along with pharmaceutically acceptable excipient(s); at time interval ranging from about 1 second to about 64800seconds; or
In another embodiment of the present disclosure, each of the compounds is in ratio ranging from about IC10 dose to IC80.
In an embodiment of the present disclosure, oncology disease system of the present disclosure is a very comprehensive representation of the bio-molecular activity involved in the solid and liquid tumors. The system includes all the pathways and bio- molecular interactions in the key phenotypes of Cancer, such as viability, apoptosis, proliferation, angiogenesis and metastasis.
In an embodiment of the present disclosure, the Virtual Tumor Cell Platform of the present disclosure consists of a dynamic and kinetic representation of the signaling pathways underlying tumor physiology at the bio-molecular level with coverage on all the key tumor phenotypes including proliferation, viability, angiogenesis, metastasis, apoptosis, tumor metabolism and tumor microenvironment related to associated inflammation. The technology is a comprehensive coverage of protein players; associated gene and mRNA species with regard to tumor related signaling. The platform subset coverage includes signaling pathways comprising growth factors like EGFR, PDGFRA, FGFR, c- ET, VEGFR. and IGF-I R, cell cycle regulators, mTOR signaling, p53 signalingcascade, cytokine pathways like ILL IL4, IL6, IL12, IL15 TNF; TGF-b, hypoxia mediated regulation, angiogenic promoters, lipid mediators and tumor metabolism and others. It has a wide coverage of kinases and transcription factors associated with tumor physiology network. The modeling of the time- dependent changes in the fluxes of the constituent pathways is done utilizing modified ordinary differential equations (ODE) and mass action kinetics. The current version of the technology includes over 6500biological species with over thirty thousand cross- talk interactions. The platform is prospectively and retrospectively validated against an extensive set of pre-defined in vitro and in vivo studies.
In an embodiment of the present disclosure, the starting control state of the system is based on normal epithelial cell physiology that is non-tumorigenic. The user can control the transition of the normal system to a neoplastic disease state aligning with specific tumor mutation profiles. This is accomplished as an example through over- expression of the tumori genie genes like EGFR, IGF-IR; knock-downs of the tumor- suppressors like p53, PTEN; and increased states of hypoxia and oxidative stress. Knockdowns or over-expressions of biological species can be done at the expression or activity levels.
In an embodiment of the present disclosure, drags are represented in this technology through explicit mechanism of action specification and the drug concentration in the virtual experiments is explicitly assumed to be post ADME (Absorption, Distribution, Metabolism, and Excretion). In an embodiment of the present disclosure, multiple virtual patient profiles are generated by overlaying the functional impact of mutations. Therapeutics that is being designed is tested against this panel of virtual patients to understand the differential sensitivity of the therapy to the multiple patient profiles. This system of testing is the first step on the road to designing and tailoring therapies for individual patients.
In an embodiment of the present disclosure, composition and the process of preparing the composition for the purpose of improving one or more undesirable symptoms associated with the disease states or for slowing the progression (worsening) of one or more symptoms associated with the disease is provided.
In an embodiment of the present disclosure, therapeutic combinations comprising at least one member of a first group and at least one member of a second group; wherein members of the first group are selected from the group consisting of an AKT inhibitor and; and members of the second group are selected from the group consisting of a Cyclooxygenase-2 inhibitor and 5 -lipoxygenase inhibitor. The therapeutic combination can comprise: at least one AKT inhibitor (CW145) and at least one Cyclooxygenase-2 inhibitor (CW168) and/or at least one 5 -lipoxygenase inhibitor (CW254).
Figure imgf000090_0001
tthhee ccoommppoossiittiioonn ooff tthhee pprreesseenntt ddiisscclloossuurree
Figure imgf000090_0002
Name: MK-2206
Drag Bank Accession No: NA
Type: Small Molecule inhibitor
Groups.Phase 2
Description: MK-2206 is an orally active allosteric Akt inhibitor that is under development for the treatment of solid tumors. MK-2206 is a highly potent and selective Akt inhibitor. It is equally potent toward purified recombinant human Aktl (IC50, 5 nmol/L) and Akt2 enzyme (IC50, 12 nmol/L) and approximately 5-fold less potent against human Akt3 (IC50, 65 nmol/L;)
Brand names: NA
Indication: NA
Pharmacodynamics: In a hair follicle assay, MK-2206 inhibited pThr246 PRAS40 to total PRAS40 ratio, with a median decrease for all post-treatment time-points of 48%; there were decreases in this ratio between baseline and individual on -treatment time- points: 6 hours (P = .03), day 7 (P = .019), and day 15 (P = .009) after MK-2206 administration. There was also evidence of inhibition in the p'Thr246 PRAS40 to total PRAS40 ratio when the analyses were limited to 13 patients in the 60-mg MTD cohort (6 hours | P .0081. day 7 ( P .028 i. and day 15 | P .025 !; Fig 2B). During MTD cohort expansion at 60 mg on alternate days, paired tumor biopsies were obtained for biomarker analysis. Nine paired post-M -2206 tumor samples were suitable for analysis by MSD electrochemiluminescence assays, and all nine pairs demonstrated evidence of inhibition of pSer473 AKT when compared with paired pretreatment samples (Figs 3A to 3C). The median decrease in pSer473 AKT was 88.8% (range, 44.9% to 95.6%; P = .015) after MK-2206 treatment, confirming target modulation. Mechanism of action :Akt inhibitor MK2206 binds to and inhibits the activity of Akt in a non-ATP competitive manner. MK-2206 inhibits phosphorylation at both Thr308 and Ser473 residues of AKT
Absorption: Slow absolution, with median time to maximum measured plasma concentration values ranging from 4 to 10 hours.
Metabolism: NA
Half-life:4() to 100 hours
Route of elimination: NA
Class of Drugs involved in this category: PER1FOSINE, Akt Inhibitor X, A-674563, API 2, AT 7867, CCT128930, FPA 124, GDC-0068, GSK690693, PHT-427, Triciribine, AZD5363, Deguelin
Manufacturers: Merck & Co. Inc.
FDA approval: MK2206 has not yet been approved by the FDA.
Figure imgf000091_0001
Name: Nelfinavir
Drug Bank Accession No:DB00220 (APRD00003)
Type: Small Molecule inhibitor
Groups: Approved
Description: Nelfinavir is an anti-viral compound that specifically inhibits the HIV aspartyl protease, a retroviral enzyme that cleaves the viral gag-pol polyprotein required for the production of infectious viral particles. This also has anti-neoplastic activity mediated through inhibition of AKT phosphorylation. At higher concentrations, Nelfinavir can inhibit the beta 2 (trypsin-like activity) subunit along with the beta 1 and beta 5 (chymotrypsin like activity) of the proteasome and induce endoplasmic reticulum stress. It is used in combination with other antiviral drugs in the treatment of H IV in both adults and children.
Brand names: Viracept
Indication: Used in combination with other antiviral drugs in the treatment of HIV in both adults and children.
Pharmacodynamics: -
HIV protease inhibitors such as Nelfmavir have been reported to cause AKT inhibition at 20 uM which is in the range of concentration of the drug achievable in plasma at therapeutically approved dosage. [PMID 23454896]. Inhibition of AKT phosphorylation at Ser473 has been reported to be an independent mechanism of drug action in this study as opposed to other papers that report AKT inhibition as a consequence of proteasome inhibition and consequent unfolded protein response. [PMID : 17460771]. However, direct/indirect inhibition of AKT by HIV protease inhibitors is well reported and has been seen in patients taking the medication.
[PMID : 18285707]
Mechanism of action: HIV protease inhibitor, AKT inhibitor, Proteasome inhibitor Absorption: Well absorbed following oral administration.
Metabolism: Primarily hepatic via cytochrome P450 (CYP450) enzymes. CYP3A and CYP2C19 appear to be the predominant enzymes that metabolize nelfmavir in humans. One major and several minor metabolites are found in plasma; the major oxidative metabolite has in vitro antiviral activity comparable to that of the parent drag.
Half-life: 3, 5 - 5 hours
Route of elimination: The terminal half-life in plasma was typically 3.5 to 5 hours.
The majority (87%) of an oral 750 nig dose containing 14C-nelfinavir was recovered in the feces; fecal radioactivity consisted of numerous oxidative metabolites (78%) and unchanged nelfmavir (22%). Only 1-2% of the dose was recovered in urine, of which unchanged nelfmavir was the major component.
Class of Drags involved in this category: Nelfmavir, tipranavir, indinavir, saquinavir, lopinavir, ritonavir, fosamprenavir, darunavir, atazanavir
Manufacturers: Hoffmann-La Roche
FDA approval: Nelfmavir is an FD A approved drug. present disclosure also envisages the use of:
® a compound not yet approved by the FDA as an AKT inhibitor,
® a compound that may be approved by the FDA at a later stage as an AKT inhibitor,
® a compound known in the art to be an AKT inhibitor but not approved by the
FDA as an AKT inhibitor, and
® a compound that might be proven at a later stage to be an AKT inhibitor, without approval by the FDA for the same.
Figure imgf000093_0001
Name: Celecoxib
Drag Bank ID: DB00482 (APRD00373)
Type: Small Molecule inhibitor
Group: approved
Dosage: Form - Capsule, Route - Oral, Strength - 50 nig, 100 mg, 200 mg, 400 mg
Description: Celecoxib is a non-steroidal anti-inflammatory drag (NSAID) used in the treatment of osteoarthritis, rheumatoid arthritis, acute pain, painful menstruation and menstrual symptoms, and to reduce numbers of colon and rectum polyps in patients with familial adenomatous polyposis.
Brand Name: Celebra, Celebrex
Indication: For relief and management of osteoarthritis (OA), rheumatoid arthritis (RA), juvenile rheumatoid arthritis (JRA), ankylosing spondylitis, acute pain, primary dysmenorrhea and oral adjunct to usual care for patients with familial adenomatous polyposis
Pharmacodynamics: Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, is classified as a nonsteroidal anti-inflammatory drug (NSAID). Celecoxib is used to treat rheumatoid arthritis, osteoarthritis, and familial adenomatous polyposis (FAP). Because of its lack of platelet effects, celecoxib is not a substitute for aspirin for cardiovascular prophylaxis. It is not known if there are any effects of celecoxib on platelets that may contribute to the increased risk of serious cardiovascular thrombotic adverse events associated with the use of celecoxib. Inhibition of PGE2 synthesis may lead to sodium and water retention through increased fluid reabsorption in the renal medullary thick ascending loop of Henle and perhaps other segments of the distal nephron. In the collecting ducts, PGE2 appears to inhibit water reabsorption by counteracting the action of antidiuretic hormone.
Mechanism of Action: The mechanism of action of celecoxib is believed to be due to inhibition of prostaglandin synthesis. Unlike most NSAIDs, which inhibit both types of cyclooxygenases (COX-1 and COX-2), Celecoxib is a selective non-competitive inhibitor of cycl.ooxygenase-2 (COX-2) enzyme, it binds with its polar sulfonamide side chain to a hydrophilic side pocket region close to the active COX-2 binding site. Both COX-1 and COX-2 catalyze the conversion of arachidonic acid to prostaglandin (PG) H2, the precursor of PGs and thromboxane.
Absorption: Well absorbed in the gastrointestinal tract. When a single dose of 200 mg is given to healthy subjects, peak plasma levels occur 3 hours after an oral dose. The peak plasma level is 705 ng/mL.Absolute bioavailability studies have not been conducted. When multiple doses are given, steady-state is reached on or before Day 5. When taken with a high fat meal, peak plasma levels are delayed for about 1 to 2 hours with an increase in total absorption (AUG) of 10% to 20%.
Metabolism: Hepatic. Celecoxib metabolism is primarily mediated through cytochrome P450 2C9. Three metabolites, a primar alcohol, the corresponding carboxylic acid and its glucuronide conjugate, have been identified in human plasma. CYP3A4 is also involved in the hydroxylalion of celecoxib but to a lesser extent. These metabolites are inactive as COX-1 or COX-2 inhibitors.
Half Life: The effective half-life is approximately 11 hours when a single 200 mg dose is given to healthy subjects. Terminal half-life is generally variable because of the low solubility of the drug thus prolonging absorption.
Route of Elimination: Celecoxib is eliminated predominantly by hepatic metabolism with little (<3%) unchanged drug recovered in the urine and feces, 57% of the oral dose is excreted in the feces and 27% is excreted into the urine, The primary metabolite in urine and feces was the carboxylic acid metabolite (73%)). The amount of glucuronide in the urine is low.
Class of Drugs involved in this category: Acemetacin, Acetaminophen, Aspirin, Diclofenac, DuP-697, Etodolac, FK-3311, Flufenamic Acid, Flurbiprofen, FR- 122047, ibuprofen, Indomethacin, Ketoprofen, Ketorolac, Naproxen, Niflumic Acid, Nimesulide, NS-398, Piroxicam, Resveratrol, Rofecoxib, SC-560, SC-58125, Sulmdac, Talniflumate, Tenidap, Valdecoxib
Manufacturers: Gdsearlellc
FDA approval: Celecoxib is an FDA approved drug.
The present disclosure also envisages the use of:
» a compound not yet approved by the FDA as aCOX-2 inhibitor,
® a compound that may be approved by the FDA at a later stage as a COX-2 inhibitor,
· a compound known in the art to be a COX-2 inhibitor but not approved by the
FDA as a COX-2 inhibitor, and
® a compound that might be proven at a later stage to be a COX-2 inhibitor, without approval by the FDA for the same.
Name: Zileuton
Drug Bank ID: DB00744 (APRD00265)
Type: Small Molecule Inhibitor
Group: approved
Dosage: Form - Tablet, Route - Oral, Strength - 600 mg
The recommended dosage of ZYFLO CR for the treatment of patients with asthma is two 600 mg extended-release tablets twice daily, within one hour after morning and evening meals, for a total daily dose of 2400 mg.
Description: Leukotrienes are substances that induce numerous biological effects including augmentation of neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, increased capillary permeability, and smooth muscle contraction. These effects contribute to inflammation, edema, mucus secretion, and bronchoconstriction in the airways of asthmatic patients. Zileuton relieves such symptoms through its selective inhibition of 5 -lipoxygenase, the enzyme that catalyzes the formation of leukotrienes from arachidonic acid. Specifically, it inhibits leiikotriene LTB4, LTC4, 1.1 1)4. and LTE4 formation. Both the R(+) and S(-) enantiomers are pharmacologically active as 5 -lipoxygenase inhibitors in in-vitro systems. Brand Name: Leutrol, Zyilo, Zyilo CR
Indication: For the prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older.
Pharmacodynamics: Zileuton is an asthma drug that differs chemically and pharmacologically from other antiasthmatic agents. It blocks leukotriene synthesis by inhibiting 5 -lipoxygenase, an enzyme of the eicosanoid synthesis pathway. Current data indicates that asthma is a chronic inflammatory disorder of the airways involving the production and activity of several endogenous inflammatory mediators, including leukotrienes. Sulfide-peptide leukotrienes (LTC4, LTD4, LTE4, also known as the slow-releasing substances of anaphylaxis) and LTB4, a chemoattractant for neutrophils and eosinophils, are derived from the initial unstable product of arachidonic acid metabolism, leukotriene A4 (LTA4), and can be measured in a number of biological fluids including bronchoalveolar lavage fluid (BALF) from asthmatic patients. In humans, pretreatment with zileuton attenuated bronchoconstriction caused by cold air challenge in patients with asthma.
Mechanism of Action: Leukotrienes are substances that induce numerous biological effects including augmentation of neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, increased capillary permeability, and smooth muscle contraction. These effects contribute to inflammation, edema, mucus secretion, and bronchoconstriction in the airways of asthmatic patients. Zileuton relieves such symptoms through its selective inhibition of 5 -lipoxygenase, the enzyme that catalyzes the formation of leukotrienes from arachidonic acid. Specifically, it inhibits leukotriene LTB4, LTC4, LTD4, and LTE4 formation. Both the R(+) and S(-) enantiomers are pharmacologically active as 5 -lipoxygenase inhibitors in in- vitro systems. Due to the role of leukotrienes in the pathogenesis of asthma, modulation of leukotriene formation by interruption of 5 -lipoxygenase activity may reduce airway symptoms, decrease bronchial smooth muscle tone, and improve asthma control.
Absorption: Rapidly and almost completely absorbed. The absolute bioavailability is unknown.
Metabolism: Hepatic. Zileuton and its N-dehydroxylated metabolite are oxidatively metabolized by the cytochrome P450 isoenzymes 1 A2, 2C9 and 3A4. Half Life: 2.5 hours
Route of Elimination: Elimination of zileuton is predominantly through metabolism with a mean terminal half-life of 2.5 hours. The urinary excretion of the inactive N- dehydroxylated metabolite and unchanged zileuton each accounted for less than 0.5% of the dose.
Class of Drags involved in this category: Bayx-1005, BW B70C, MK886, PD 146176, STEARDA, 2-TEDC
Manufacturers: Cornerstone Therapeutics Inc
FDA approval: Zileuton is an FDA approved drug.
The present disclosure also envisages the use of:
* a compound not yet approved by the FDA as an ALOX5 inhibitor,
• a compound that may be approved by the FDA at a later stage as an ALOX5 inhibitor,
» a compound known in the art to be an inhibitor but not approved by the FDA as an ALOX5 inhibitor, and
» a compound that might be proven at a later stage to be an ALOX5 inhibitor, without approval by the FDA for the same, Cancer and Associated Conditions and Methods of" Treatment
In an embodiment, the present disclosure provides a process for preparing a composition, the composition comprising one or more compounds, wherein the compounds are CW145, CW168 and CW254, wherein the composition optionally comprises a pharmaceutically-acceptable excipient, wherein the process comprises the step of combining the compounds and the optional excipient in any order thereof.
In an embodiment, the disclosure described herein provides therapeutic methods for the treatment of cancer and associated conditions, or combinations thereof. In one embodiment of the present disclosure, the disclosure provides a method for treating a subject either suspected of having or having a condition or mutation or a combination thereof!, wherein said condition is selected from a group comprising cancers with PTEN/PI3K/AKT mutations including lung cancer, colorectal cancer, pancreatic cancer, glioblastoma, multiple myeloma etc or any combination of conditions thereof, or wherein said mutation co-occurs with each other or with other cancer promoting mutations such as those in genes similar but not limited to EGFR, KRAS, NRAS, B-catenin, CD N2A, P13K.CA, APC, MYC, BCL2, SOCS1, SMAD4, TP53 or any combination of mutations thereof, said method comprising act of administering to the subject a combination of - a) therapeutically-effective amount of an AKT inhibitor and atleast one of b) therapeutically-effective amount of a Cyclooxygenase-2 inhibitor and a 5 -lipoxygenase inhibitor; and wherein the administration uses one or a plurality of dosage forms, each dosage form comprising one or more inhibitors, and wherein each dosage form optionally comprises a pharmaceuticaliy-acceptabie excipient.
In an embodiment, the disclosure provides a use of a composition in the preparation of a medicament for the treatment of cancer and associated conditions, the composition comprising: an AKT inhibitor and at least one of a Cyclooxygenase-2 inhibitor anda 5 -lipoxygenase inhibitor.
In an embodiment of the present disclosure, pharmaceutical compositions containing compounds described herein are administered for prophylactic and/or therapeutic treatments. In therapeutic applications, the compositions are administered to a subject already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition, or to cure, heal, improve, or ameliorate the condition itself. Amounts effective for this use can vary based on the severity and course of the disease or condition, previous therapy, the subject's health status, weight, and response to the drugs, and the judgment of the treating physician. Pharmaceuticaliy-acceptabie amounts are determined by routine experimentation, for example, by a dose escalation clinical trial.
In an embodiment of the present disclosure, multiple therapeutic agents are administered in any order or simultaneously. If simultaneously, the multiple therapeutic agents are provided in a single, unified form, or in multiple forms, for example, as multiple separate pills. The compounds are packed together or separately, in a single package or in a plurality of packages. One or all of the therapeutic agents are given in multiple doses. If not simultaneous, the timing between the multiple doses may vary to as much as about a month. In anembodiment, composition of the disclosure is administered sequentially at a time interval. The time interval ranges from about 1 second to about 800minut.es.
In an embodiment, compositions of the disclosure are packaged as a kit. In an embodiment, a kit includes written instructions on the use of the composition. The instructions can provide information on the identity of the therapeutic agent(s), modes of administration, or the indications for which the therapeutic agent(s) are used.
In an embodiment, therapeutics are combined with genetic or genomic testing to determine whether that individual is a carrier of a mutant gene that is known to be correlated with certain diseases or conditions. A personalized medicine approach may be used to provide companion diagnostic tests to discover a subject's predisposition to certain conditions and susceptibi lity to therapy. For example, a subject who is an anti- EGFR non responder may be identified through companion diagnostics. The companion diagnostic test can be performed on a tumor biopsy. Instructions on the use of a companion diagnostic test are provided on written material packaged with a compound, composition, or kit of the disclosure. The written material may be, for example, a label. The written material may suggest conditions or genetic features relevant to inflammation or the therapeutic compounds of the disclosure. The instructions provide the subject and the supervising physician with the best guidance for achieving the optimal clinical outcome from the administration of the therapy.
In an embodiment, compounds/composition described herein are administered before, during, or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound may vary. For example, the compounds are used as a prophylactic and are administered continuously to subjects with a propensity to conditions or diseases in order to prevent the occurrence of the disease or condition. The compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms. The administration of the compounds may be initiated within the first 48 hours of the onset of the symptoms, within the first 24 hours of the onset of the symptoms, within the first 6 hours of the onset of the symptoms, or within 3 hours of the onset of the symptoms. The initial administration may be through any route practical, such as by any route described herein using any formulation described herein, A compound may be administered as soon as is practicable after the onset of a disease or a condition is detected or suspected, and for a length of time necessary for the treatment of the disease, such as, for example, from about 1 month to about .3 months. The length of treatment may vary for each subject, and the length can be determined using the known criteria.
EXAMPLES
The present disclosure is further elucidated by the following illustrative, non-limiting examples. As used in predictive and experimental Figures (1 - 11) and references to the same: CW145 is MK2206 or Neifmavir (AKT inhibitor); CW168 is Ceiecoxib (COX inhibitor); CW254 is Zileuton (LOX inhibitor).
In examples 2 - 4, CW 145 is MK2206 and in examples 5 - 7, CW145 is Nelfinavir. EXAMPLE 1 ; Virtual Tumor Based In-vivo aligned studies of Therapies of" the Disclosure
In an embodiment, the compositions of the disclosure were analyzed on a virtual tumor cell system designed to represent the disease state, and customized to match a specific molecular profile of specific cancer baselines. These experiments are validated by the experiment provided below.
The baselines selected for the virtual experiments include:
a) U251 human glioblastoma cell line harboring mutation in PTEN and TP53 b) U87 human glioblastoma cell line harboring mutation in PTEN with wild type TP53;
c) LN229 human glioblastoma cell line harboring mutation in TP53
In these virtual experiments, the system was first triggered with the respective oncogenic mutations aligned to the specific profiles and then simulated for a minimum of about 35 hours simulation time. The simulation time was selected to allow the system to attain the severe oncogenic state through activation of autocrine and paracrine pathway loops affecting all oncogenic mediators like growth factors, kinases and transcription factors. After about 35 hours of simulation time, a system customized to the above mentioned tumor profi le is created.
The drug compounds CW145 CW254 and CW168 individually or in combinations were administered concomitantly to the Virtual Tumor cell, and the system simulated again for a minimum of about 18-20 hours simulation time. The drag administration was performed at multiple dosage ratios across an array of samples for each drug. The effect of the multiple dosage ratios was evaluated after about 1 8-20 hours of simulation time by assaying the extent of decrease/increase in the tumor cell survival, apoptosis and proliferation markers. The major markers assayed include active complexes of CDK4-CCND1, CDK2-CCNE, CDK2-CCNA and CDK1-CCNB1 responsible for cell proliferation. Other proteins including BCL2, BIR.C5, BIRC2, BAX, CASP3 and PARPl cleaved were assayed to determine their effect on tumor cell survival and apoptosis. Other vital biomarkers including VEGFA were assayed to estimate the levels of angiogenesis.
Based on the assayed biomarkers, an overall viability score was calculated as a ratio of survi val/apoptosis. "Viability" is a scale to measure change in tumorogenic symptoms. A reduction greater than 25% is considered as being moderately effective and a reduction greater than 40% is considered being an effective therapy.
Viability index is a ratio of cumulative measure of an average of survival over apoptotic markers. It is defined as a ratio of the cumulative survival index over the apoptosis index. The survival index comprises of AKT1, BCL2, BIRC5, BIRC2, MCLl and XIAP, end point markers. The apoptosis index comprises of BAX, CASP3, PMAIP1, CASP8, and BCL2L11. Proliferation index is a cumulative measure of an average of cell cycle checkpoint complexes comprising of CD 4-CCND1 , CDK2-CCNE, CDK2-CCNA and CDK1 -
CCNB1 active complexes,
The combinations of compounds described herein provide therapeutic benefits at low dosage, including synergistic benefits.
Figure 1 illustrates the impact of different combination of drugs (CW145-CW168, CW145-CW254, CW145-CW168-CW254) on a Non-triggered normal epithelial cell Figure 2 illustrates the impact of combination of drags on PTEN Mutated and PTEN wild-type cell lines. The impact including phenotypic indexes (viability index and proliferation index) for the cell lines U251 (PTEN and P53 profile and U87 (PTEN profile). Here the concentration of drug is at IC20 for two drugs and three drugs, IC2o is the concentration of dnig that causes 20% reduction in viability in PTEN mutated profile.
Figure 3ill.ustrates the impact of combination of drugs on PTEN Mutated Cell lines with respect to the biomarker levels (CASP3, PARP1 Cleaved, CDK2-CCNE, CDK4- CCND1, RHEB-GTP and RPS6). It is seen that the two and three drug combinations of CW145 along with CW168 and CW254 increase the levels of apoptotic markers like CASP3 and PARP1. Further, the said two and three drug combinations decreases the levels of biomarkers such as CDK2-CCNE, CDK4-CCND1, RHEB-GTP and RPS6.
Figure illustrates scientific rationales for the different combination therapies and its impact on the key phenotypes of PTEN driven cancer.
Figure Sillustrates the enhancement of efficacy by combining variable doses of drug CW145 with a fixed dose of drug CW168 and drag CW254 in combination on key phenotype - Viability, Proliferation in PTEN mutated cell lines
EXPERIMENTAL DATA Table 4:
Figure imgf000102_0001
187 - PTEN Mutation, CD N2A deleted, CDKN2C deleted; EGFR amplified, P53 wild type
LN229 - P53 mutated, CDKN2A, CDKN2B deleted, NF1 low, c-MET high, PTEN Wild type.
Figure imgf000103_0001
EXAMPLES 2-7
Below table 6 briefly illustrates the description of the examples 2-7 and their respective figures
Figure imgf000103_0002
Bar plot illustrating the effect of CW145 alone and in combination with at least one of CW168 and CW254 in
Example .3 U251MG human glioma cell line. Drugs were tested Figure 7
alone and in combination at 0. 5μ CW145, 25μΜ and
50 μΜ CW168 and 50μΜ CW254.
Bar plot illustrating the effect of CW145 alone and in
combination with at least one of CW168 and CW254 in
Example 4 U87 human glioma cell line and LN229 human glioma Figure 8
cell line. Drags were tested alone and in combination at
0. 5μΜ CW145, 25μΜ CW168 and 50μΜ CW254
Bar plot illustrating the effect of CW145 alone and in
combination with at least one of CW168 and CW254 in
Example 5 U251 human glioma cell line. Drugs were tested alone Figure 9
and in combination at 20 μΜ CW145, 20 μΜ CW168
and 50 μΜ CW254.
Bar plot illustrating the effect of CW145 alone and in
combination with at least one of CW168 and CW254 in
Example 6 U87 human glioma cell line. Drugs were tested alone Figure 10 and in combination at 20 μΜ CW145, 20 μΜ CW168
and 50 μΜ CW254.
Bar plot illustrating the effect of CW145 alone and in
combination with at least one of CW168 and CW254 in
Example 7 U251 human glioma cell line and LN229 human glioma Figure 11 cell line. Drags were tested alone and in combination at
15 μΜ CW145, 20μΜ CW168 and 50μΜ CW254.
EXAMPLE 2
Bar plot illustrating the effect of CW145 alone and in combination with at least one of CW168 and CW254 in U251MG human glioma cell line.
U251 MG human glioma cell line is procured from Sigma-Aldrich (Catalog number: 09063001). The cells are resuspended in a media containing 10% FBS (Gibco lot# 1259720) and 4X Gentamicin followed by transferring about 100 μΐ to each well in an assay plate (3,100 cells/well; passage# 6). DMSO, Digi toxin and drugs (CW145, CW168 and CW254 individually and in combinations) are serial diluted in an assay media. 100 μΐ/well of the diluted sample is added to assay plate containing resuspended cells. Final assay volume of each well is about 200 μΐ, containing 10% FBS, 2X Gentamicin, DMSO, Digitoxin and drags. The assay plate is incubated for about 71 hours ibllowed by addi tion of about 20 μΐ of Promega Substrate Cei lTiter 96 Aqueous One Solution Reagent to each well. It is incubated at 37°C, The absorbance of the sample is read at about 490 nm.
Results
Figure 6 illustrates concentrations of drags individually, 2 dimensional and 3 dimensional combinations on the x-axis and percentage change in relative growth on the y-axis. The individual concentrations of the drags used is 5 μΜ for CW145, 50 μΜ for CW168 and 100 μΜ for CW254 and at these concentrations, the individual drugs do not show much efficacy. The drugs were combined in 2 dimensional combination at lowered doses of l/10th of CW145 at 0.5 μΜ; half of CW168 at 25 μΜ and half of CW 254 at 50 μΜ. The two dimensional combination at lowered doses shows a slightly better efficacy when compared to the individual drugs alone and when combined as a 3 dimensional combination of CW145 at 0.5μΜ, CW168 at 25 μΜ and CW254 at 50 μΜ, a synergistic -60% reduction in relative growth is noted that is not seen at higher concentrations of the drugs individually. This indicates that the combination of drugs shows synergistic efficacy. Further, the example indicates that the drugs are used at lower doses when used in combination in comparison to the doses when used individually.
EXAMPLE 3
Bar plot illustrating the effect of CW145 alone and in combination with at least one of CW168 and CW254 in U251MG human glioma cell line.
U251 MG human glioma cell line is procured from Si.gma-Aldri.ch (Catalog number: 09063001). The cells are resuspended in a media containing 10% FBS (Gibco lot# 1259720) and 4X Gentamicin followed by transferring about 100 μΐ to each well in an assay plate (3,100 cells/well; passage# 6). DMSO, Digitoxin and drags (CW145, CW168 and CW254 individually and in combinations) are serial diluted in an assay media, 100 μΐ/well of the diluted sample is added to assay plate containing resuspended cells. Final assay volume of eac well is about 200 μΐ, containing 10% FBS, 2X Gentamicin, DMSO, Digitoxin and drugs. The assay plate is incubated for about 7 hours followed by addition of about 20 μ ί of Promega Substrate CellTiter 96 Aqueous One Solution Reagent to each well. It is incubated at 37°C. The absorbance of the sample is read at about 490 nm.
Results
Figure 7 illustrates different dose combinations of CW145:CW168:CW254 that shows synergistic efficacy when combined together. CW145 at 0.5 μΜ when combined with CW168 at 25 μΜ and CW254 at 50 μΜ reduces relative growth synergistically by 60% when compared to minimal reduction in relative growth with the individual drags and when combined as a 2 dimensional combination. In the combination, when CW168 is increased to 50 μΜ keeping the other drug concentrations the same as before, there is an almost 99%) reduction in relative growth making this 3D combination very efficacious and synergistic.
EXAMPLE 4
Bar plot illustrating the effect of CW145 alone and in combination with at least one of CW168 and CW254 in U87 and LN229 human glioma cell line.
The U87 human glioma cell line is procured from ATCC (American Type Culture Collection, Manassas, VA, ΑΤίΧ; ΗΤΒ-14™). PTEN WT LN229 cell line is procured from ATCC (American Type Culture Collection, Manassas, VA, ATCC® CRL-2611 '"). The cells are resuspended in a media containing 10% FBS (Gibco lot# 1259720) and 4X Gentamicin followed by transferring about 100 μΐ to each well in an assay plate (3,000 cells/well; passage# 10). DMSO, Digitoxin and drags (CW145, CW168 and CW254 individually and in combinations) are serial diluted in an assay media. 100 μΐ/well of the diluted sample is added to assay plate containing resuspended cells. Final assay volume of each well is about 200 μΐ, containing 10% FBS, 2X Gentamicin, DMSO, Digitoxin and drugs. The assay plate is incubated for about 71 hours followed by addition of about 20 μΐ of Promega Substrate CeilTiter 96 Aqueous One Solution Reagent to each well. It is incubated at 37°C and absorbance of the sample is read at about 490 nm.
Results
Figure 8 illustrates the comparison of the effect of the combination in PTEN Null U87 Cells and PTEN WT LN229 cells when combined at the same concentration of CW145 at 0.5uM, CW168 at 25uM and CW254 at 50 uM. The reduction with the 2 dimensional and 3 dimensional combination is much higher in PTEN Null U87 cells when compared to PTEN WT LN229 cells. With the combination of the 3 drugs, there is a synergistic relative growth reduction of -60% in PTEN Null U87 cells while the relative growth reduction in the PTEN WT LN229 cells is only about 35%.
EXAMPLE 5
Bar plot illustrating the effect of CW145 alone and in combination with at least one of CW168 and CW254 in U251MG human glioma cell line,
U251MG human glioma cell line is procured from Sigma- Aldrich (Catalog number: 09063001 ). The cells are resuspended in a media containing 10% FBS (Gibco lot# 1259720) and 4X Gentamicin followed by transferring about 100 ul to each well in an assay plate (3,100 cells/well; passage# 6). DMSO, Digitoxin and dnigs (CW145, CW168 and CW254 individually and in combinations) are serial diluted in an assay media. 100 μΐ/well of the diluted sample is added to assay plate containing resuspended cells. Final assay volume of each well is about 200 μΐ, containing 10% FBS, 2X Gentamicin, DMSO, Digitoxin and drugs. The assay plaste is incubated for about 71 hours followed by addition of about 20 μΐ of Promega Substrate CeilTiter 96 Aqueous One Solution Reagent to each well. It is incubated at 37°C. The absorbance of the sample is read at about 490 nm.
Results
Figure 9 illustrates that when the cells are incubated with the each of the drugs alone at the indicated concentrations, CW145 (20 μιιΜ), CW168 (20μιτΜ) or CW254 (50μυΜ), there is small decrease in cell viability showing -65% with CW145. However there is negligible effect seen with CW168 and CW254 showing -120% relative growth with each drug alone. Further, treatment with two drug combinations at the said concentrations resulted in better effect seen on cell survival , showing -40% relative growth in case of CW145 (20 μΜ) and CW168 (20μΜ) combination and -57% relative growth in case of CW145 (20 μΜ) and CW254 (50μΜ) combination. Insignificant decrease in relative growth was seen with CW168 (20μΜ) and CW254 (5()μΜ) combination, being -83% relative growth, incubation of the cells with the three drugs in combination at the same concentrations showed drastic effect with relative growth of about 30%.
EXAMPLE 6
Bar plot illustrating the effect of CW145 alone and in combination with at least one of CW168 and CW254 in U87 human glioma cell line
The U87 human glioma cell line is procured from ATCC (American Type Culture Collection, Manassas, VA, ATCC*' HTB-14' "), The cells are resuspended in a media containing 10% FBS (Gibco lot# 1259720) and 4X Gentamicin followed by transferring about 100 ul to each well in an assay plate (3,000 cells/well; passage# 10), DMSO, Digitoxin and drugs (CW145, CW 168 and CW254 individually and in combinations) are serial diluted in an assay media. 100 μΐ/well of the diluted sample is added to assay plate containing resuspended cells. Final assay volume of each well is about 200 μΐ, containing 10% FBS, 2X Gentamicin, DMSO, Digitoxin and drugs. The assay plate is incubated for about 71 hours followed by addition of about 20 μΐ of Promega Substrate CellTiter 96 Aqueous One Solution Reagent to each well. It is incubated at 37°C and absorbance of the sample is read at about 490 nm.
Results
Figure 10 illustrates that when the cells are incubated with the each of the drugs alone at the indicated concentrations, CW145 (20 μΜ), CW 168 (20μΜ) or CW254 (50μΜ), there is insignificant decrease in cell viability showing -80% with CW145. However there is no effect seen with CW168 and CW254, showing -100% relative growth with each drug alone. Further, treatment with two drug combinations at the said concentrations resulted in better effect seen on cell survival , showing -70% relative growth in case of CW145(20 μΜ) and CW168 (20μΜ) combination . -80% relative growth in case of CW145 (20 μΜ) and CW254 (50μΜ) combination and also in case of CW168 (20μΜ) and C W254 (50μΜ) combination. Incubation of the cells with the three drugs in combination at the same concentrations showed drastic effect with relative growth of about 60%.
EXAMPLE 7-
Bar plot illustrating the effect of CW145 alone and in combination with at least one of CW168 and CW254 in U251 and LN229 human glioma cell line.
U251MG human glioma cell line is procured from Sigma-Aldrich (Catalog number: 09063001 ). PTEN WT LN229 cell line is procured from ATCC (American Type Culture Collection, Manassas, VA, ATCC® CRL-2611 " ). The cells are resuspended in a media containing 10% FBS (Gibco lot# 1259720) and 4X Gentamicin followed by transferring about 100 ul to each well in an assay plate (3,100 cells/well; passage# 6). DMSO, Digitoxin and drugs (CW145, CW168 and CW254 individually and in combinations) are serial diluted in an assay media. 100 μΐ/well of the diluted sample is added to assay plate containing resuspended cells. Final assay volume of each well is about 200 μΐ, containing 10% FBS, 2X Gentamicin, DMSO, Digitoxin and drags. The assay plate is incubated for about 71 hours followed by addition of about 20 μΐ of Promega Substrate CellTiter 96 Aqueous One Solution Reagent to each well. It is incubated at 37'JC. The absorbance of the sample is read at about 490 nm.
Results
Figure 11 illustrates the comparison of the effect of the combination in PTEN Null U251 Cells and PTEN WT LN229 cells when combined at the same concentration of CW145 at 15 μΜ, CW168 at 20μΜ and CW254 at 50 uM. The reduction with the 2 dimensional and 3 dimensional combinations are much higher in PTEN Null U251 cells when compared to PTEN WT LN229 cells. With the combination of the 3 drugs, there is a synergistic relative growth reduction of -40% in PTEN Null U251 cells while the relative growth reduction in the PTEN WT LN229 cells is only about 20%>,
CONCLUSION:
From the above experimental results in U251MG, U87 and LN229 human glioma cell lines, it is evident that the two drug as well as three drug combinations of AKT inhibitor (CW 145) and atleast one of COX-2 inhibitor (CW168) and 5-LOX inhibitor (CW254) are effective in reducing the cell survival. Further, the three drug combination of CW145, CW168 and CW254 shows the best effect in decreasing the cell survival suggesting that they are most eflective in treatment of cancers caused due to PTEN/AKT/PI3K mutations.

Claims

1. A composition comprising: i) an AKT inhibitor; and ii) at least one of cyclooxygenase-2 inhibitor and 5-lipoxygenase inhibitor; optionally along with a pharmaceutically acceptable excipient.
2. The composition as claimed in claim 1, wherein the composition comprises an AKT inhibitor and cyclooxygenase-2 inhibitor optionally along with a pharmaceutically acceptable excipient.
3. The composition as claimed in claim 1 , wherein the composition comprises an AKT inhibitor and 5-lipoxygenase inhibitor optionally along wit a pharmaceutically acceptable excipient.
4. The composition as claimed in claim 1, wherein the composition comprises an AKT inhibitor, cyclooxygenase-2 inhibitor and 5-lipoxygenase inhibitor optionally along with a pharmaceutically acceptable excipient.
5. The composition as claimed in claim 1, wherein the AKT inhibitor is selected from a group comprising compound of:
Formula 1(a):
Figure imgf000111_0001
wherein R is halogen, I I and R2 are alkyl or hydrogen Formula 1(b):
Figure imgf000112_0001
wherein R3, R4, R5, R6 are hydrogen or alkyl
Formula 1 (c):
Figure imgf000112_0002
wherein R7, R8, R9, RIO, Rl 1 , R12 are alkyl or hydrogen Formula 1(d):
Figure imgf000112_0003
wherein R13, R14 are alkyl or hydrogen, R15 is halogen
Formula 1(e):
Figure imgf000113_0001
wherein R16, R17, R18 are alkyl or hydrogen, R19 is halogen
Formula 1(f):
Figure imgf000113_0002
wherein R20 is halogen, R21, R22, R23 are alkyl or hydrogen
Formula 1(g):
Figure imgf000114_0001
wherein R24, R25, R26, R27, R29 are alkyl or hydrogen, R28 is halogen Formula 1(h):
Figure imgf000114_0002
wherein R30, R31 ,R33, R35, R36 are alkyl or hydrogen; R32, R34 are alkyl
Formula l (i):
Figure imgf000115_0001
wherein R37, R38, R39 are alkyl or hydrogen Formula l(j):
Figure imgf000115_0002
wherein R40, R41 , R42 are alkyl or hydrogen
Formula l(k):
Figure imgf000115_0003
wherein R43, R44 are alkyl or hydrogen Formula 1(1):
Figure imgf000116_0001
wherein R45, R46, R47, R48, R49, R50 are alkyl or hydrogen
Formula l(m):
Figure imgf000116_0002
wherein R51, R52, R53, R54,R56 are alkyl or hydrogen; R55 is halogen Formula l(n):
Figure imgf000117_0001
Figure imgf000117_0002
Zl, Z2, 73, Z4, Z5,Z6,Z7, Z8, Z9, Z10 are alkyl or hydrogen Formula l(p):
Figure imgf000118_0001
wherein Zl l, Z12, Z13, Z14, Z15, Z16 are alkyl or hydrogen Formula l(q):
Figure imgf000118_0002
wherein Z17, Z19, Z20, Z21 are alkyl or hydrogen; Z18 is halogen Formula l(r):
Figure imgf000119_0001
wherein Z22, Z23, Z24, Z25, Z26, Z27 and Z28 are alkyl or hydrogen Formula l(s):
Figure imgf000119_0002
wherein Z29, Z30, Z31 , Z32, Z33, Z34, Z35, Z36, Z37, Z38, Z39 are alkyl or hydrogen
Formula l(t):
Figure imgf000120_0001
Figure imgf000120_0002
wherein Z48, Z49, Z50, Z51, Z52, Z53, Z54 are alkyl or hydrogen
Formula l(v):
Figure imgf000121_0001
wherein Z55, Z56, Z57, Z58, Z59, Z60, Z61 are hydrogen or alkyl Formula l(w):
Figure imgf000121_0002
wherein Z62, Z63, Z64, Z65, Z66, Z67, Z68 are hydrogen or alkyl Formula l(x):
Figure imgf000122_0001
wherein Z69, Z70, Z71 , Z72, Z73, Z74, Z75, Z76, Z77 are Hydrogen or Alkyl Formula l (y):
Figure imgf000122_0002
wherein Z78, Z79, Z80, Z81 , Z82, Z83 are alkyl or hydrogen; a pharmaceutically-acceptable salt of any of the foregoing and combination thereof.
6. The composition as claimed in claim 2, wherein the AKT inhibitor selected from a group comprising compounds of formula l(o), l(p), l(q), l(r), l(s), l(t), l(u), l(v), l (w), l (x) and l(y) is also an HIV protease inhibitor.
7. The composition as claimed in claim 1, wherein the Cyclooxygenase-2 inhibitor is selected from a group comprising compounds of:
Formula 2(a):
Figure imgf000123_0001
wherein XI , X2 and X3 are hydrogen or alkyl; X is halogen
Formula 2(b):
Figure imgf000123_0002
wherein X4 and X5 are hydrogen or alkyl
Formula 2(c):
Figure imgf000124_0001
wherein X6. X7 are alkvl or hydrogen
Formula 2(d):
Figure imgf000124_0002
wherein X8 is halogen; X9, X10, Xl l are alkvl or hydrogen
Formula 2(e):
Figure imgf000124_0003
wherein XI 2, XI 3 are alkvl or hydrogen; X14 is halogen
Formula 2(f):
Figure imgf000125_0001
wherein X17, X18, X19, X20 are alkyl or hydrogen
Formula 2(h):
Figure imgf000125_0002
wherein X21 is halogen; X22, X23, X24 are alkyl or hydrogen Formula 2(i):
Figure imgf000126_0001
wherein X25 is halogen, X26, X27 are alkyl or hydrogen Formula 2(j):
Figure imgf000126_0002
wherein X28 is halogen; X29, X30, X31 are alkyl or hydrogen
Formula 2(k):
Figure imgf000126_0003
wherein X32, X33, X34 are alkyl or hydrogen
Formula 2(1):
Figure imgf000127_0001
wherein X35, X36, X37 are alkyl or hydrogen
Formula 2(m):
Figure imgf000127_0002
wherein X38 is halogen, X39,X40, X41 are alkyl or hydrogen
Formula 2(n):
Figure imgf000127_0003
wherein X42, X43 are hydrogen or alkyl
Formula 2(o):
Figure imgf000128_0001
wherein X46, X47 are alkyl or hydrogen
Formula 2(q):
Figure imgf000128_0002
wherein X48, X49 are alkyl or hydrogen; X50 is halogen Formula 2(r):
Figure imgf000129_0001
wherein X51is cycloalkyi or aryl; X52, X53 are alkyl or hydrogen
Formul a 2(s):
Figure imgf000129_0002
erein X54, X55, X56 are alkyl or hydrogen
Formula 2(t):
wherein X57, X58, X59, X60, X61 are alkyl or hydrogen
Formula 2(u):
Figure imgf000130_0001
wherein X62 is alkyl or hydrogen
Figure imgf000130_0002
wherein X63, X64 are halogen; X65 is selected from alkoxy, alkyl siilfonyl and hydrogen
Formula 2(w):
Figure imgf000131_0001
wherein X66, X67, X68, X69 are alkyl or hydrogen and X70 is halogen
Formula 2(x):
Figure imgf000131_0002
wherein X71 is halogen and X72 is alley! or hydrogen
Formul a 2(y):
Figure imgf000132_0001
wherein X73, X74, X75 are hydrogen or alkyl and X76 is halogen
Formula 2(z):
Figure imgf000132_0002
wherein X77, X78, X79 are alkyl or hydrogen
Formula 2(al ):
Figure imgf000132_0003
wherein X80, X81, X82 are alkyl or hydrogen; X83 is halogen;
a pharmaceutically-acceptable salt of any of the foregoing and combination thereof.
8. The composition as claimed in claim 1, wherein the 5-lipoxygenas selected from a group comprising compounds of:
Formula 3(a):
Figure imgf000133_0001
wherein Yl is alky! or hydrogen
Formula 3(b):
Figure imgf000133_0002
wherein Y2, Y3, Y4, Y5, Y7, Y 8 are alkyl or hydrogen; Y6 is halogen
Formula 3(c):
Figure imgf000134_0001
wherein Yl l is halogen; Y9, Y10, Y12, Y13, Y14 are alkyl or hydrogen Formula 3(d):
Figure imgf000134_0002
wherein Y15 is hydrogen or alkyl
Formula 3(e):
Figure imgf000134_0003
wherein Y16, Y17, Y 18, Y19 are alkyl or hydrogen
Formula 3(f):
Figure imgf000135_0001
wherein Y20, Y21 are alkyl or hydrogen Formula 3(g):
Figure imgf000135_0002
wherein Y22, Y23,Y24, Y25 are aikyi or hydrogen; a pharmaceutically-acceptable salt of any of the foregoing and combination thereof,
9. The composition as claimed in claim 1 , wherein the pharmaceutically-acceptable excipient is a granulating agent, binding agent, lubricating agent, disintegrating agent, sweetening agent, glidant, anti-adhereni, anti-static agent, surfactant, anti -oxidant, gum, coating agent, coloring agent, flavouring agent, coating agent, plasticizer, preservative, suspending agent, emulsifying agent, plant cellulosic material, spheronization agent, immediate release agent, controlled release agent, sustained delayed release agent or combination thereof.
10. The composition as claimed in claim 1, wherein the composition is in a dosage form selected from a group comprising feed, food, pellet, lozenge, liquid, elixir, aerosol, inhalant, spray, powder, tablet, pill, capsule, gel, geltab, nanosuspension, nanoparticle, microgel, suppository troches, aqueous or oily suspensions, ointment, patch, lotion, dentifrice, emulsion, cream, drop, dispersible powder or granule, emulsion in hard or soft gel capsule, syrup, phytoceutical, nutraceutical and combination thereof.
11. The composition as claimed in claim 1 , wherein the composition is a dosage form having an immediate release, a controlled release or a sustained delayed release mechanism.
12. The composition as claimed in claim 1, wherein the composition is a dosage form formulated for mode of administration selected from a group comprising intravenous, subcutaneous, intramuscular, oral, rectal, aerosol, parenteral, ophthalmic, pulmonary, transdermal, vaginal, otic, nasal, topical administration and combination thereof.
13. A process of preparing the composition as claimed in claim 1, said process comprising act of: combining an AKT inhibitor and atleast one of Cycl.ooxygenase-2 inhibitor and 5-lipoxygenase inhibitor optionally along with a pharmaceutically acceptable excipient in any ratio, any concentration or any order thereof to obtain the composition as claimed in claim 1.
14. A kit comprising: i. an AKT inhibitor; and ii. atleast one of Cyclooxygenase-2 inhibitor and 5-lipoxygenase inhibitor: optionally along with a pharmaceutically acceptable excipient as claimed in claim 1.
15. A method of treating cancer and associated conditions in a subject in need thereof, the method comprising administering to a subject a composition claimed in claim 1 comprising: i) a therapeutically-effective amount of an AKT inhibitor; and
ii) a therapeutically-effective amount of atleast one of Cyclooxygenase-2 inhibitor and 5-lipoxygenase inhibitor;
optionally along with a pharmaceutically acceptable excipient, wherein the administration uses one or a plurality of dosage forms.
16. Use of a composition claimed in claim 1 in the preparation of a medicament for the treatment of cancer and associated conditions, the composition comprising: i) an AKT inhibitor and ii) atleast one of cyclooxygenase-2 inhibitor and 5-lipoxygenase inhibitor; optionally along with a pharmaceutically acceptable excipient as claimed in claim 1. 17, The method and use as claimed in claims 15 or 16, wherein the cancer and associated conditions are caused by mutation in PTEN/PI3K/AKT alone or in combination with each other or in combination with mutation in other genes causing cancer,
18, The method and use as claimed in claims 15 or 16, wherein the cancer is selected from a group comprising glioblastoma multiforme, endometrial cancer, ovarian cancer, prostate cancer, breast cancer, lung cancer, colorectal cancer, pancreatic cancer, brain cancer, head and neck cancer, glioblastoma, multiple myeloma, acute non lymphocytic leukemia and myelodysplasia, or combination of conditions thereof.
19, The method and use as claimed in claims 15 or 16, wherein the therapeutically effective amount of the AKT inhibitor is from about 10% to about 100% of a maximum tolerated dose; the therapeutically effecti ve amount of the cyclooxygenase- 2 inhibitor is from about 10% to about 100% of a maximum tolerated dose; and the therapeutically effective amount of the 5-lipoxygenase inhibitor is from about 10% to about 100%) of a maximum tolerated dose.
20, The method and use as claimed in claims 15 or 16, wherein the therapeutically effective amount of the AKT inhibitor is from about 1 mg to about 3000 mg; the therapeutically effective amount of the cyclooxygenase-2 inhibitor is from about 1 mg to about 3000 mg; and the therapeutically effective amount of the 5-lipoxygenase inhibitor is from about 1 mg to about 3000 mg.
21 , A method of inhibiting cancer cells/inducing cytotoxicity in cancer cells modulating markers in cancer cells, said method comprising act of contacting the cancer cells with a composition comprising: i. an AKT inhibitor; and ii. atleast one of Cyclooxygenase-2 inhibitor and 5-lipoxygenase inhibitor; optionally along with a pharmaceutically acceptable excipient as claimed in claim 1 ,
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