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WO2025163633A1 - Thérapies synergiques pour le traitement du cancer - Google Patents

Thérapies synergiques pour le traitement du cancer

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Publication number
WO2025163633A1
WO2025163633A1 PCT/IL2025/050092 IL2025050092W WO2025163633A1 WO 2025163633 A1 WO2025163633 A1 WO 2025163633A1 IL 2025050092 W IL2025050092 W IL 2025050092W WO 2025163633 A1 WO2025163633 A1 WO 2025163633A1
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WIPO (PCT)
Prior art keywords
compound
combination
formula
cancer
subject
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Pending
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PCT/IL2025/050092
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English (en)
Inventor
Max Herzberg
Yuval Sagiv
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Vidac Pharma Ltd
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Vidac Pharma Ltd
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Publication of WO2025163633A1 publication Critical patent/WO2025163633A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/86—Carbazoles; Hydrogenated carbazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/38—[b, e]-condensed with two six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D335/10—Dibenzothiopyrans; Hydrogenated dibenzothiopyrans
    • C07D335/12—Thioxanthenes
    • C07D335/20—Thioxanthenes with hydrocarbon radicals, substituted by amino radicals, directly attached in position 9
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention provides combination therapies for treating cancer, said therapies comprising a piperazine derivative and a chemotherapeutic or targeted therapy agent, methods for their preparation, pharmaceutical compositions including such compounds, and methods of using these compounds, especially for targeted therapy of hyperproliferative disorders, including benign hyperproliferative disorders, cancers and pre-cancerous conditions.
  • Cancer remains a significant global health challenge, with an estimated 10 million cancer deaths per year. Despite significant advancements in cancer treatment, the overall survival rate remains suboptimal, and there is an urgent need for novel therapeutic strategies to improve outcomes for cancer patients.
  • combination drug therapy in cancer treatment has emerged as a promising strategy to combat the heterogeneity and adaptability of cancer cells.
  • combination therapy aims to enhance antitumor efficacy while mitigating the development of drug resistance.
  • a method for treating a cancer or other hyperproliferative disorder in a subject in need thereof comprising providing to said subject:
  • U and Z are each independently N or CH;
  • X is O, NH, S, or a bond
  • R 2 and R 3 are each independently at each occurrence selected from the group consisting of halogen, NO2, CN, C1-C4 alkyl, OR 4 , and NR 5a R 5b ;
  • R 4 , R a , R 5a , and R 5b are each independently hydrogen or C1-C4 alkyl; n is 0 or 1; m is 0, 1, or 2; p and q are each independently selected from 0, 1, 2, 3, and 4; or a pharmaceutically acceptable salt thereof; and
  • a method for treating a cancer or other hyperproliferative disorder in a subject in need thereof comprising providing to said subject a compound represented by Formula (23): or a salt thereof; and (b) cisplatin or a salt thereof.
  • a method for treating a cancer or other hyperproliferative disorder in a subject in need thereof comprising providing to said subject a compound represented by Formula (23): or a salt thereof; and (b) sorafenib or a salt thereof.
  • a method of increasing cisplatin anti-tumor effect in a subject in need thereof comprising providing to said subject a compound represented by Formula (23): or a pharmaceutically acceptable salt thereof.
  • a method for reducing tumor cell viability comprising providing to a subject a composition comprising a compound represented by Formula (23): and cisplatin, or pharmaceutically acceptable salts thereof.
  • a method for reducing tumor cell viability comprising providing to a subject a composition comprising a compound represented by Formula (23): and sorafenib, or pharmaceutically acceptable salts thereof.
  • a pharmaceutical composition comprising a compound represented by Formula (23): and cisplatin, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a compound represented by Formula (23): and sorafenib, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable earner.
  • FIG. 1 Dose-dependent effect of Compound (23) on cancer proliferation and viability (dark section of each column) in vitro. HepG2 cells (10,000/well) were treated with increasing concentrations of Compound (23). After 72 h, cells were tested for proliferation using EdU staining and live cells were determined by DRAQ7 staining.
  • Figure 2A Dose-dependent effect of sorafenib on liver cancer cell proliferation (squares) and viability (circles). HepG2 cells (10,000/well) were treated with increasing concentrations of sorafenib and were stained with EdU staining and DRAQ7 after 72 h.
  • Figure 2B Dose-dependent effect of cisplatin on liver cancer cell proliferation (squares) and viability (circles). HepG2 cells (10,000/well) were treated with increasing concentrations of cisplatin and were stained with EdU staining and DRAQ7 after 72 h.
  • FIGS. 4A-4E The effect of treatment with Compound (23) and/or cisplatin on tumor growth inhibition on day 38.
  • Mice were treated with cisplatin (1 or 0.5 mg/kg, twice a week), Compound (23) (400mg/kg PO, QD), or with a combination of cisplatin and Compound (23).
  • Significant TGI was shown in animals treated with cisplatin 0.5 mg/kg + Compound (23), cisplatin 1 mg/kg alone, and cisplatin 1 mg/kg + Compound (23), with the combination treatment having the strongest effect.
  • FIG. 5 The probability of survival for animals treated with Compound (23) and/or cisplatin over the first 50 days of the experiment. A significant increase in survival probability was shown in animals treated with cisplatin 1 mg/kg + Compound (23) compared to vehicle-administered animals, p-value ⁇ 0.0041 .
  • a method for treating a cancer or other hyperproliferative disorder in a subject in need thereof by providing a compound of Formula (II) and a chemotherapeutic and/or a targeted therapy agent to the subject.
  • treating a cancer comprises blocking cancer cell proliferation, inducing apoptosis in cancer cells, decreasing cancer cell viability, creating a pro-inflammatory environment within a tumor, or a combination thereof.
  • a method for inhibiting a cancer or other hyperproliferative disorder in a subject in need thereof by providing a compound of Formula (II) and a chemotherapeutic and/or a targeted therapy agent to the subject.
  • a method for suppressing a cancer or other hyperproliferative disorder in a subject in need thereof by providing a compound of Formula (II) and a chemotherapeutic and/or a targeted therapy agent to the subject.
  • a method for treating, inhibiting, or suppressing a cancer or other hyperproliferative disorder in a subject in need thereof comprising providing to said subject a compound represented by the structure of Formula (II) and a chemotherapeutic agent.
  • disclosed herein is a method for increasing the anti-tumor effect of a chemotherapeutic agent in a subject in need thereof, said method comprising providing to said subject a compound represented by the structure of Formula (II).
  • a method for synergistically increasing the anti-tumor effect of a chemotherapeutic agent in a subject in need thereof said method comprising providing to said subject a compound represented by the structure of Formula (II).
  • a method for treating, inhibiting, or suppressing a cancer or other hyperproliferative disorder in a subject in need thereof comprising providing to said subject a compound represented by the structure of Formula (II) and a targeted therapy agent.
  • disclosed herein is a method for increasing the anti-tumor effect of a targeted therapy in a subject in need thereof, said method comprising providing to said subject a compound represented by the structure of Formula (II).
  • a method for synergistically increasing the anti-tumor effect of a targeted therapy in a subject in need thereof said method comprising providing to said subject a compound represented by the structure of Formula (II).
  • a method for decreasing the viability of hyperproliferative cells in a subject having a hyperproliferative disorder said method comprising providing to said subject a compound represented by the structure of Formula (II) and a chemotherapeutic agent.
  • disclosed herein is a method for synergistically decreasing the viability of hyperproliferative cells in a subject having a hyperproliferative disorder, said method comprising providing to said subject a compound represented by the structure of Formula (II) and a chemotherapeutic agent.
  • a method for synergistically increasing the inhibition of cancer cell viability in a subject comprising providing to said subject a compound represented by the structure of Formula (II) and a chemotherapeutic agent.
  • disclosed herein is a method for decreasing the viability of hyperproliferative cells in a subject having a hyperproliferative disorder, said method comprising providing to said subject a compound represented by the structure of Formula (II) and a targeted therapy.
  • a method for synergistically decreasing the viability of hyperproliferative cells in a subject having a hyperproliferative disorder said method comprising providing to said subject a compound represented by the structure of Formula (II) and a targeted therapy.
  • disclosed herein is a method for synergistically increasing the inhibition of cancer cell viability in a subject.
  • disclosed herein is a method for decreasing the viability of cancer cells in a subject having a hyperproliferative disorder, said method comprising providing to said subject a compound represented by the structure of Formula (II) and a chemotherapeutic and/or a targeted therapy agent.
  • a method for synergistically decreasing the viability of cancer cells in a subject having a hyperproliferative disorder said method comprising providing to said subject a compound represented by the structure of Formula (II) and a chemotherapeutic and/or a targeted therapy agent.
  • disclosed herein is a method for synergistically increasing the inhibition of cancer cell viability in a subject.
  • disclosed herein is a method for blocking cancer cell proliferation by providing a compound of Formula (II) and a chemotherapeutic and/or a targeted therapy agent to a subject in need thereof.
  • a method for inducing apoptosis in cancer cells by providing a compound of Formula (II) and a chemotherapeutic and/or a targeted therapy agent to a subject in need thereof.
  • a method for changing the inflammatory environment within a tumor by providing a compound of Formula (II) and a chemotherapeutic and/or a targeted therapy agent to a subject in need thereof.
  • the change in the inflammatory environment within a tumor is the creation of a pro-inflammatory environment.
  • disclosed herein is a method for decreasing cancer cell viability by providing a compound of Formula (II) and a chemotherapeutic and/or a targeted therapy agent to a subject in need thereof.
  • disclosed herein is a method for blocking cancer cell proliferation by providing Compound (23) and a chemotherapeutic agent to a subject in need thereof.
  • a method for inducing apoptosis in cancer cells by providing Compound (23) and a chemotherapeutic agent to a subject in need thereof.
  • a method for changing the inflammatory environment within a tumor by providing Compound (23) and a chemotherapeutic agent to a subject in need thereof.
  • the change in the inflammatory environment within a tumor is the creation of a pro-inflammatory environment.
  • disclosed herein is a method for decreasing cancer cell viability by providing Compound (23) and a chemotherapeutic agent to a subject in need thereof.
  • disclosed herein is a method for blocking cancer cell proliferation by providing Compound (23) and a targeted therapy or targeting agent to a subject in need thereof.
  • a method for inducing apoptosis in cancer cells by providing Compound (23) and a targeted therapy or targeting agent to a subject in need thereof.
  • a method for changing the inflammatory environment within a tumor by providing Compound (23) and a targeted therapy or targeting agent to a subject in need thereof.
  • the change in the inflammatory environment within a tumor is the creation of a pro-inflammatory environment.
  • disclosed herein is a method for decreasing cancer cell viability by providing Compound (23) and a targeted therapy or targeting agent to a subject in need thereof.
  • a method for changing the inflammatory environment within a tumor by providing Compound (23) and cisplatin to a subject in need thereof.
  • the change in the inflammatory environment within a tumor is the creation of a pro-inflammatory environment.
  • a method for inducing apoptosis in cancer cells by providing Compound (23) and sorafenib to a subject in need thereof.
  • disclosed herein is a method for changing the inflammatory environment within a tumor by providing Compound (23) and sorafenib to a subject in need thereof.
  • the change in the inflammatory environment within a tumor is the creation of a pro-inflammatory environment.
  • disclosed herein is a method for decreasing cancer cell viability by providing Compound (23) and sorafenib to a subject in need thereof.
  • “providing” a compound to a subject comprises administering the compound to the subject.
  • administering the compound is via parenteral administration, intravenous administration, oral administration, rectal administration, intranasal administration, topical administration, or administration by inhalation.
  • treating refers to ameliorating or causing regression of the disease or the symptoms of the disease; inhibiting the disease or arresting its development; or preventing the symptoms or disease from occurring in a subject that is predisposed or does not yet display symptoms of the disease.
  • treatment is an approach for obtaining beneficial or desired results, including clinical results.
  • beneficial or desired results can include one or more, but are not limited to, alleviation or amelioration of one or more symptoms, diminishment of extent of a condition, stabilizing (i.e., not worsening) state of a condition, delay or slowing of condition, progression, amelioration or palliation of the condition, states and remission (whether partial or total), whether detectable or undetectable.
  • cancer refers to cells that have undergone a malignant transformation that makes them pathological to the host organism.
  • Non-limiting examples of cancers that may be treated according to the methods of the present disclosure include a solid tumor or a non-solid tumor.
  • a “subject” refers to an organism that can benefit from receiving a treatment comprising a chemotherapeutic and/or a targeted therapy agent, cisplatin, or sorafenib.
  • the term subject refers to a cancer patient.
  • the term subject refers to a human with predisposition to develop a malignancy.
  • the term subject refers to a human being.
  • the term subject refers to an animal.
  • the term “subject” refers to any organism who is suffering or at risk of a disease or disorder or condition. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and/or humans). In some embodiments, a subject is a human. In some embodiments, a subject is suffering from or susceptible to one or more diseases or disorders or conditions. In some embodiments, a subject displays one or more symptoms of a disease or disorder or condition. In some embodiments, a subject has been diagnosed with one or more diseases or disorders or conditions, which, in some embodiments, is amenable to the technologies described herein.
  • Tumors for which the present treatment methods are useful include any malignant cell type, such as those found in a solid tumor or a hematological or non-solid tumor.
  • Exemplary solid tumors can include, but are not limited to, a tumor of an organ selected from the group consisting of pancreas, colon, cecum, stomach, brain, head, neck, ovary, kidney, larynx, sarcoma, lung, bladder, melanoma, prostate, and breast.
  • Exemplary hematological tumors include tumors of the bone marrow, T or B cell malignancies, leukemias, lymphomas, blastomas, myelomas, and the like.
  • cancers that may be treated using the methods provided herein include, but are not limited to, lung cancer (including small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous carcinoma of the lung), cancer of the peritoneum, gastric or stomach cancer (including gastrointestinal cancer and gastrointestinal stromal cancer), pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, various types of head and neck cancer, skin cancer, bone cancer, and melanoma.
  • lung cancer including small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous carcinoma of the lung
  • cancer of the peritoneum gastric or stomach cancer (including gastrointestinal cancer and gastrointestinal stromal cancer)
  • pancreatic cancer cervical cancer, ovarian cancer, liver cancer, bladder cancer,
  • the solid tumor comprises a colon cancer, which in some embodiments, comprise adenocarcinoma.
  • the colon cancer comprises primary colorectal lymphomas, gastrointestinal stromal tumors, leiomyosarcomas, carcinoid tumors, melanomas, or a combination thereof.
  • the solid tumor comprises a liver cancer, which in some embodiments, comprise hepatocellular carcinoma (HCC; hepatoma), cholangiocarcinoma (bile duct cancer), and angiosarcoma.
  • HCC hepatocellular carcinoma
  • cholangiocarcinoma bile duct cancer
  • angiosarcoma angiosarcoma
  • the cancer comprises a lymphoproliferative disorder. In other embodiments, the cancer comprises a cancer of the central nervous system or cancer of the peripheral nervous system.
  • a non-solid tumor as described herein comprises a hematologic cancer, acute myelogenous leukemia, acute myelocytic leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, mast cell leukemia, multiple myeloma, myeloid lymphoma, Hodgkin’s lymphoma, nonHodgkin’s lymphoma, cutaneous T-cell lymphoma, or metastases thereof.
  • the cancer may specifically be of the following histological type, though it is not limited to these: neoplasm, malignant; carcinoma; carcinoma, undifferentiated; giant and spindle cell carcinoma; small cell carcinoma; papillary carcinoma; squamous cell carcinoma; lymphoepithelial carcinoma; basal cell carcinoma; pilomatrix carcinoma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; gastrinoma, malignant; cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellular carcinoma and cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma in adenomatous polyp; adenocarcinoma, familial polyposis coli; solid carcinoma; carcinoid tumor, malignant; branchiolo-alveolar adenocarcinoma; papillary adenocarcinoma; chromophobe carcinoma;
  • the cancer is multiple myeloma. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is AML. In other embodiments, the cancer comprises an esophageal carcinoma, a thyroid carcinoma, ganglioblastoma, osteogenic sarcoma, endotheliosarcoma, Ewing’s tumor, leimyosarcoma, rhabdotheliosarcoma, invasive ductal carcinoma, papillary adenocarcinoma, adenocarcinoma, renal cell carcinoma, hypernephroma, hypemephroid adenocarcinoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms’ tumor, testicular tumor, lung carcinoma, bladder carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealo
  • At least one further agent effective at treating cancer is administered to said subject.
  • radiation therapy is administered to said subject.
  • methods for treating, inhibiting, or suppressing a cancer or other hyperproliferative disorder in a subject in need thereof comprising providing to said subject
  • U and Z are each independently N or CH;
  • X is O, NH, S, or a bond
  • R 2 and R 3 are each independently at each occurrence selected from the group consisting of: halogen, NO2, CN, C1-C4 alkyl, OR 4 , and NR 5a R 5b ;
  • R 4 , R a , R 5a , and R 5b are each independently hydrogen or C1-C4 alkyl; n is 0 or 1; m is 0, 1, or 2; p and q are each independently selected from 0, 1, 2, 3, and 4; or a pharmaceutically acceptable salt thereof; and (b) a chemotherapeutic and/or a targeted therapy agent.
  • R 2 is H. In some embodiments, R 3 is H. In other embodiments, R 2 is H and R 3 is H. In some embodiments, in the compound of Formula (II), p is 0. In some embodiments, q is 0. In other embodiments, p is 0 and q is 0. In some embodiments, in the compound of Formula (II), U is N.
  • the compound provided in the methods disclosed herein, and together with a chemotherapeutic and/or a targeted therapy agent is represented by the structure of Formula (III): wherein X, U, R 1 , R 2 , R 3 , m, n, p, and q are defined as described herein; and a chemotherapeutic and/or a targeted therapy agent.
  • X is O, NH, or a bond. In some embodiments, X is O. In other embodiments, X is a bond. In certain embodiments, X is NH.
  • R 1 is aryl or heteroaryl.
  • R 1 is phenyl, quinolinyl, or isoquinolinyl.
  • R 1 is phenyl, optionally substituted with one or more halogen, CN, C1-C4 alkyl, OR 4 , or a combination thereof.
  • R 2 is H. In some embodiments, R 3 is H. In other embodiments, R 2 is H and R 3 is H. [059] In some embodiments, in the compound of Formula (III), p is 0. In some embodiments, q is 0. In other embodiments, p is 0 and q is 0.
  • the compound provided in the methods disclosed herein is represented by the structure of Formula (IV). wherein X, U, R 1 , R 2 , R 3 , m, n, p, and q are defined as described herein.
  • X is O. In other embodiments, X is S. In certain embodiments, X is NH.
  • R 1 is aryl or heteroaryl.
  • R 1 is phenyl, quinolinyl, or isoquinolinyl.
  • R 1 is phenyl, optionally substituted with one or more halogen, CN, C1-C4 alkyl, OR 4 , or a combination thereof.
  • R 2 is H. In some embodiments, R 3 is H. In other embodiments, R 2 is H and R 3 is H.
  • p is 0.
  • q is 0.
  • p is 0 and q is 0.
  • the compound provided together with a chemotherapeutic and/or a targeted therapy agent as disclosed in the methods, compositions, and combinations disclosed herein is: [068] In other embodiments, the compound is:
  • the compound is: [070] In other embodiments, the compound is:
  • the compound is: [072] In other embodiments, the compound is:
  • the compound is:
  • the compound is:
  • the compound is:
  • the compound is:
  • the compound is a combination of the compounds above.
  • the compounds described may be salts, hydrates, solvates, polymorphs, optical isomers, geometrical isomers, enantiomers, diastereomers, or mixtures of the compounds.
  • the compound provided together with a chemotherapeutic and/or a targeted therapy agent as disclosed in the methods, compositions, and combinations disclosed herein is represent by Formula (V): wherein X, U, R 1 , R 2 , R 3 , m, n, p, and q are defined as described herein.
  • Z is N. In other embodiments,
  • R 1 is aryl or heteroaryl.
  • R 1 is phenyl, quinolinyl, or isoquinolinyl.
  • R 1 is phenyl, optionally substituted with one or more halogen, CN, C1-C4 alkyl, OR 4 , or a combination thereof.
  • R 2 is H.
  • R 3 is H. In other embodiments, R 2 is H and R 3 is H.
  • p is 0.
  • q is 0.
  • p is 0 and q is 0.
  • the compound provided together with a chemotherapeutic and/or a targeted therapy agent as disclosed in the methods, compositions, and combinations disclosed herein is:
  • the compound is:
  • the compound is:
  • the compound is: [087] In some embodiments, the compound is a combination of the compounds above. In some embodiments, the compounds described may be salts, hydrates, solvates, polymorphs, optical isomers, geometrical isomers, enantiomers, diastereomers, or mixtures of the compounds.
  • the compound provided together with a chemotherapeutic and/or a targeted therapy agent as disclosed in the methods, compositions, and combinations disclosed herein is represented by the structure of Formula (VI):
  • R 1 is aryl or heteroaryl.
  • R 1 is phenyl, quinolinyl, or isoquinolinyl.
  • R 1 is phenyl, optionally substituted with one or more halogen, CN, C1-C4 alkyl, OR 4 , or a combination thereof.
  • R 2 is H.
  • R 3 is H. In other embodiments, R 2 is H and R 3 is H.
  • p is 0.
  • q is 0.
  • p is 0 and q is 0.
  • the compound provided together with a chemotherapeutic and/or a targeted therapy agent as disclosed in the methods, compositions, and combinations disclosed herein is:
  • R 1 is selected from the group consisting of phenyl, quinolinyl and isoquinolinyl, each of which may independently be unsubstituted or substituted with one or more halogen, OR a or NR a R b wherein R a and R b are each independently selected from the group consisting of H or a C1-C4 alkyl.
  • X is S.
  • Z is CH.
  • R 1 is aryl, optionally substituted with one or more alkyl, arylalkyl, halogen, NO 2 , CN, OR 4 , and NR 5a R 5b , or a combination thereof.
  • R 1 is aryl substituted with one or more alkyl, arylalkyl, halogen, NO2, CN, OR 4 , and NR 5a R 5b , or a combination thereof.
  • R 1 is aryl substituted with one or more alkyl, arylalkyl, halogen, NO2, and NR 5a R 5b , or a combination thereof.
  • R 1 is phenyl substituted with one or more alkyl, arylalkyl, halogen, NO2, and NR 5a R 5b , or a combination thereof. In some embodiments wherein X is S, R 1 is aryl, optionally substituted with one or more halogen and C1-C4 alkyl, or a combination thereof. In some embodiments wherein X is S, R 1 is phenyl, optionally substituted with one or more halogen and C1-C4 alkyl, or a combination thereof.
  • R 1 is heteroaryl, optionally substituted with one or more alkyl, arylalkyl, halogen, NO2, CN, OR 4 , and NR 5a R 5b , or a combination thereof. In some embodiments wherein X is S, R 1 is not pyridinyl. In some embodiments wherein X is S, R 1 is heteroaryl substituted with one or more alkyl, arylalkyl, halogen, NO2, CN, OR 4 , and NR 5a R 5b , or a combination thereof.
  • R 1 is heteroaryl substituted with one or more alkyl, arylalkyl, halogen, NO2, and NR 5a R 5b , or a combination thereof.
  • R 1 is quinolinyl, or isoquinolinyl.
  • R 1 is quinolinyl or isoquinolinyl, optionally substituted with one or more alkyl, arylalkyl, halogen, NO2, CN, OR 4 , and NR 5a R 5b , or a combination thereof.
  • the compound is represented by the structure of Formula (II), wherein n is 0. According to this aspect and in one embodiment, the compound is represented by the structure of Formula (II-a):
  • the compound is represented by Formula (II), wherein p and q are each 0 (i.e., R 2 and R 3 do not exist).
  • an “alkyl” group refers to any saturated aliphatic hydrocarbon, including straight-chain and branched-chain alkyl groups.
  • the alkyl group has 1-4 carbons designated here as C1-C4 -alkyl.
  • the alkyl group has 1-7 carbons designated here as Ci-C?-alkyl.
  • the alkyl group may be unsubstituted or substituted by one or more groups selected from halogen, hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxyl, thio and thioalkyl.
  • aryl used herein alone or as part of another group denotes an aromatic ring system containing from 6-14 ring carbon atoms.
  • the aryl ring can be a monocyclic, bicyclic, tricyclic and the like.
  • Non-limiting examples of aryl groups are phenyl, naphthyl including 1- naphthyl and 2-naphthyl, and the like.
  • the aryl group can be unsubstituted or substituted through available carbon atoms with one or more groups defined hereinabove for alkyl.
  • heteroaryl used herein alone or as part of another group denotes a heteroaromatic system containing at least one heteroatom ring atom selected from nitrogen, sulfur and oxygen.
  • the heteroaryl contains 5 or more ring atoms. In some embodiments, the heteroaryl group contains 5-10 ring atoms.
  • the heteroaryl group can be monocyclic, bicyclic, tricyclic and the like. Also included in this expression are the benzoheterocyclic rings. If nitrogen is a ring atom, the present invention also contemplates the N-oxides of the nitrogen containing heteroaryls.
  • heteroaryls include thienyl, benzothienyl, 1- naphthothienyl, thianthrenyl, furyl, benzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, purinyl, quinolyl (e.g.
  • the heteroaryl group can optionally be substituted through available atoms with one or more groups defined hereinabove for alkyl.
  • the heteroaryl group can be unsubstituted or substituted through available atoms with one or more groups defined hereinabove for alkyl.
  • halogen or "halo” as used herein alone or as part of another group refers to chlorine, bromine, fluorine, and iodine.
  • alkoxy refers to the group OR a wherein R a is a C1-C4 alkyl as defined above.
  • R a is a C1-C4 alkyl as defined above.
  • Nonlimiting examples of an alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and like groups.
  • All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form.
  • the compounds of the present invention can have asymmetric centers at any of the atoms. Consequently, the compounds can exist in enantiomeric or diastereomeric forms or in mixtures thereof.
  • the present invention contemplates the use of any racemates (i.e. mixtures containing equal amounts of each enantiomers), enantiomerically enriched mixtures (i.e., mixtures enriched for one enantiomer), pure enantiomers or diastereomers, or any mixtures thereof.
  • the chiral centers can be designated as R or S or R,S or d,D, 1,L or d,l, D,L.
  • the present invention intends to encompass all structural and geometrical isomers including cis, trans, E and Z isomers.
  • salt encompasses both basic and acid addition salts, including but not limited to, carboxylate salts or salts with amine nitrogens, and include salts formed with the organic and inorganic anions and cations discussed below. Furthermore, the term includes salts that form by standard acid-base reactions with basic groups (such as amino groups) and organic or inorganic acids.
  • Such acids include hydrochloric, hydrofluoric, trifluoroacetic, sulfuric, phosphoric, acetic, succinic, citric, lactic, maleic, fumaric, palmitic, cholic, pamoic, mucic, D-glutamic, D- camphoric, glutaric, phthalic, tartaric, lauric, stearic, salicylic, methanesulfonic, benzenesulfonic, sorbic, picric, benzoic, cinnamic, and like acids.
  • Each possibility represents a separate embodiment of the invention.
  • organic or inorganic cation refers to counter-ions for the anion of a salt.
  • the counter-ions are chosen from the alkali and alkaline earth metals, (such as lithium, sodium, potassium, barium, aluminum and calcium); ammonium and mono-, di- and tri-alkyl amines such as trimethylamine, cyclohexylamine; and the organic cations, such as dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, bis(2- hydroxyethyl)ammonium, phenylethylbenzylammonium, dibenzylethylene diammonium, and like cations. See, for example, “Pharmaceutical Salts,” Berge et al., J. Pharm. Sci., 66: 1-19 (1977), which is incorporated herein by reference.
  • the present invention also includes solvates of the compounds of the present invention and salts thereof.
  • “Solvate” means a physical association of a compound of the invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates and the like. “Hydrate” is a solvate wherein the solvent molecule is water.
  • the present invention also includes polymorphs of the compounds of the present invention and salts thereof.
  • polymorph refers to a particular crystalline state of a substance, which can be characterized by particular physical properties such as X-ray diffraction, IR spectra, melting point, and the like.
  • compositions comprising the compounds of Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Compound (23), Compounds (l)-(2), (4)-(5), (11)-(16), or Compound (3).
  • a method for treating, inhibiting, or suppressing a cancer or other hyperproliferative disorder in a subject in need thereof comprising providing to said subject a compound represented by the structure of Formula (II) and a chemotherapeutic agent.
  • a method for increasing the anti-tumor effect of a chemotherapeutic agent in a subject in need thereof comprising providing to said subject a compound represented by the structure of Formula (II).
  • a method for synergistically increasing the anti-tumor effect of a chemotherapeutic agent in a subject in need thereof comprising providing to said subject a compound represented by the structure of Formula (II).
  • chemotherapeutic agent which can also be termed “antineoplastic agent” or “cytotoxic drug”, having all the same limitations and features, are a diverse group of pharmacological compounds employed to treat cancer. Any chemotherapeutic agent can be used in combination with a compound represented by the structure of Formula (II).
  • a chemotherapeutic agent comprises an alkylating agent. In some embodiments, a chemotherapeutic agent comprises an antimetabolite. In some embodiments, a chemotherapeutic agent comprises an antitumor antibiotic. In some embodiments, a chemotherapeutic agent comprises a hormonal agent. In some embodiments, the chemotherapeutic agent comprises an alkylating agent, an antimetabolite, an antitumor antibiotic, a hormonal agent, or a combination thereof. In some embodiments, the chemotherapeutic agent is selected from the group consisting of an alkylating agent, an antimetabolite, an antitumor antibiotic, a hormonal agent, and a combination thereof.
  • the alkylating agent comprises cisplatin, Cyclophosphamide, Carboplatin, Etoposide, Melphalan, or a combination thereof.
  • the alkylating agent is selected from the group consisting of cisplatin, Cyclophosphamide, Carboplatin, Etoposide, and Melphalan.
  • the antimetabolite is selected from the group consisting of Methotrexate, 5 -fluorouracil (5-FU), Mercaptopurine, Cytosine arabinoside (Ara-C), and Cladribine.
  • the antimetabolite comprises Methotrexate, 5 -fluorouracil (5-FU), Mercaptopurine, Cytosine arabinoside (Ara-C), Cladribine, or a combination thereof.
  • the antitumor antibiotic comprises Actinomycin D, Dactinomycin, Doxorubicin, Bleomycin, Mitomycin C, or a combination thereof.
  • the antitumor antibiotic is selected from the group consisting of Actinomycin D, Dactinomycin, Doxorubicin, Bleomycin, and Mitomycin C.
  • the hormonal agent comprises Tamoxifen, Anastrozole, Letrozole, Exemestane, Fulvestrant, or a combination thereof. In some embodiments, the hormonal agent is selected from the group consisting of Tamoxifen, Anastrozole, Letrozole, Exemestane, and Fulvestrant.
  • the methods comprise administering a compound of Formula (II) and cisplatin. In some embodiments, the methods comprise administering a compound of Formula (II) and Cyclophosphamide. In some embodiments, the methods comprise administering a compound of Formula (II) and Carboplatin. In some embodiments, the methods comprise administering a compound of Formula (II) and Etoposide. In some embodiments, the methods comprise administering a compound of Formula (II) and Melphalan.
  • the methods comprise administering a compound of Formula (II) and Methotrexate. In some embodiments, the methods comprise administering a compound of Formula (II) and 5 -fluorouracil (5-FU). In some embodiments, the methods comprise administering a compound of Formula (II) and Mercaptopurine. In some embodiments, the methods comprise administering a compound of Formula (II) and Cytosine arabinoside (Ara- C). In some embodiments, the methods comprise administering a compound of Formula (II) and Cladribine.
  • the methods comprise administering a compound of Formula (II) and Actinomycin D. In some embodiments, the methods comprise administering a compound of Formula (II) and Dactinomycin. In some embodiments, the methods comprise administering a compound of Formula (II) and Doxorubicin. In some embodiments, the methods comprise administering a compound of Formula (II) and Bleomycin. In some embodiments, the methods comprise administering a compound of Formula (II) and Mitomycin C.
  • the methods comprise administering a compound of Formula (II) and Tamoxifen. In some embodiments, the methods comprise administering a compound of Formula (II) and Anastrozole. In some embodiments, the methods comprise administering a compound of Formula (II) and Letrozole. In some embodiments, the methods comprise administering a compound of Formula (II) and Exemestane. In some embodiments, the methods comprise administering a compound of Formula (II) and Fulvestrant.
  • the methods comprise administering a compound of Formula (II) and Trastuzumab. In some embodiments, the methods comprise administering a compound of Formula (II) and Erlotinib. In some embodiments, the methods comprise administering a compound of Formula (II) and Gefitinib. In some embodiments, the methods comprise administering a compound of Formula (II) and Imatinib. In some embodiments, the methods comprise administering a compound of Formula (II) and Rituximab.
  • a method for treating a cancer in a subject in need thereof comprising providing to said subject a compound represented by the structure of Formula (II) and an immune therapy or immunotherapy.
  • the immunotherapy comprises administration of Ipilimumab, Pembrolizumab, Nivolumab, Atezolizumab, Durvalumab, or a combination thereof.
  • the immunotherapy is selected from the group consisting of Ipilimumab, Pembrolizumab, Nivolumab, Atezolizumab, and Durvalumab.
  • the methods comprise administering a compound of Formula (II) and Ipilimumab.
  • the methods comprise administering a compound of Formula (II) and Pembrolizumab. In some embodiments, the methods comprise administering a compound of Formula (II) and Nivolumab. In some embodiments, the methods comprise administering a compound of Formula (II) and Atezolizumab. In some embodiments, the methods comprise administering a compound of Formula (II) and Durvalumab.
  • the methods comprise administering a composition represented by Formula (II), a first chemotherapeutic agent, and a second chemotherapeutic agent. In some embodiments, the methods comprise administering a composition represented by Formula (II), and two or more chemotherapeutic agents.
  • the methods comprise administering a composition represented by Formula (II), a first chemotherapeutic agent, and a further cancer therapy not comprising chemotherapy. In some embodiments, the methods comprise administering a composition represented by Formula (II), a first chemotherapeutic agent, and radiotherapy.
  • the present disclosure provides compositions comprising a chemotherapeutic agent, which in one embodiment, is cisplatin. In other embodiments, the present disclosure provides compositions comprising a compound represented by the structure of Formula (II), which in one embodiment, is Compound (23), and a chemotherapeutic agent, which in one embodiment, is cisplatin.
  • a method for treating, inhibiting, or suppressing a cancer or other hyperproliferative disorder in a subject in need thereof comprising providing to said subject a compound represented by the structure of Formula (II) and a targeted therapy agent.
  • disclosed herein is a method for increasing the anti-tumor effect of a targeted therapy in a subject in need thereof, said method comprising providing to said subject a compound represented by the structure of Formula (II).
  • a method for synergistically increasing the anti-tumor effect of a targeted therapy in a subject in need thereof said method comprising providing to said subject a compound represented by the structure of Formula (II).
  • the targeted therapy agent comprises Sorafenib, Trastuzumab, Erlotinib, Gefitinib, Imatinib, Rituximab, or a combination thereof.
  • the targeted therapy agent is selected from the group consisting of Sorafenib, Trastuzumab, Erlotinib, Gefitinib, Imatinib, and Rituximab.
  • the targeted therapy agent comprises Sorafenib.
  • the targeted therapy agent comprises Trastuzumab.
  • the targeted therapy agent comprises Erlotinib.
  • the targeted therapy agent comprises Gefitinib.
  • the targeted therapy agent comprises Imatinib.
  • the targeted therapy agent comprises Rituximab.
  • the targeted therapy agent comprises a combination of the above targeted therapy agents.
  • a targeted therapy for cancer which can also be termed “precision medicine”, “molecularly targeted therapy”, or “personalized cancer therapy”, having all the same limitations and features, refers to therapeutic approaches aimed at interfering with molecular processes that distinctly occur in cancer cells.
  • targeted therapies do not affect non-malignant cells.
  • a targeted therapy targets cells having a genetic mutation.
  • a targeted therapy comprises targeting cells overexpressing oncoproteins.
  • a targeted therapy targets cells with abnormal signaling pathways.
  • the methods disclosed herein comprise administering a compound of Formula (II) and a tyrosine kinase inhibitor (TKI). In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and imatinib. In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and erlotinib. In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and sunitinib.
  • TKI tyrosine kinase inhibitor
  • the methods disclosed herein comprise administering a compound of Formula (II) and a proteasome inhibitor. In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and bortezomib.
  • the methods disclosed herein comprise administering a compound of Formula (II) and a monoclonal antibody. In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and an epidermal growth factor receptor (EGFR) inhibitor. In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and cetuximab. In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and trastuzumab.
  • EGFR epidermal growth factor receptor
  • the methods disclosed herein comprise administering a compound of Formula (II) and programmed cell death protein- 1 (PD-1) inhibitors. In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and pembrolizumab. In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and nivolumab.
  • PD-1 programmed cell death protein- 1
  • the methods disclosed herein comprise administering a compound of Formula (II) and a hormone therapy. In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and a selective estrogen receptor modulator (SERM). In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and an aromatase inhibitor. In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and tamoxifen. In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and letrozole.
  • SERM selective estrogen receptor modulator
  • the methods disclosed herein comprise administering a compound of Formula (II) and an androgen receptor blocker. In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and enzalutamide.
  • the methods disclosed herein comprise administering a compound of Formula (II) and an apoptosis inducer. In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and a Bel -2 inhibitor. In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and venetoclax.
  • the methods disclosed herein comprise administering a compound of Formula (II) and an angiogenesis inhibitor. In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and a vascular endothelial growth factor (VEGF) inhibitor. In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and bevacizumab.
  • VEGF vascular endothelial growth factor
  • the methods disclosed herein comprise administering a compound of Formula (II) and an immunotherapy. In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and chimeric antigen receptor T (CAR-T) cells.
  • CAR-T chimeric antigen receptor T
  • the methods disclosed herein comprise administering a compound of Formula (II) and checkpoint inhibitors. In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and PARP inhibitors. In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and olaparib.
  • a compound represented by the structure of Formula (II) is provided to a subject in need thereof with two chemotherapeutic and/or targeted therapy agents disclosed herein. In some embodiments, a compound represented by the structure of Formula (II) is provided to a subj ect in need thereof with three chemotherapeutic and/or targeted therapy agents disclosed herein. In some embodiments, a compound represented by the structure of Formula (II) is provided to a subject in need thereof with more than three chemotherapeutic and/or targeted therapy agents disclosed herein.
  • a method for treating a cancer or other hyperproliferative disorder in a subject in need thereof comprising providing to said subject a compound represented by the structure of Formula (III) as described hereinabove and a chemotherapeutic agent, a targeted therapy agent, an immunotherapy, or a combination thereof as described hereinabove.
  • a method for treating a cancer or other hyperproliferative disorder in a subject in need thereof comprising providing to said subject a compound represented by the structure of Formula (IV) as described hereinabove and a chemotherapeutic agent, a targeted therapy agent, an immunotherapy, or a combination thereof as described hereinabove.
  • a method for treating a cancer or other hyperproliferative disorder in a subject in need thereof comprising providing to said subject compound (1), compound (2), compound (4), compound (5), compound (11), compound (12), compound (13), compound (14), compound (15), compound (16) as described hereinabove and a chemotherapeutic agent, a targeted therapy agent, an immunotherapy, or a combination thereof as described hereinabove.
  • a method for treating a cancer or other hyperproliferative disorder in a subject in need thereof comprising providing to said subject a compound represented by the structure of Formula (V) as described hereinabove and a chemotherapeutic agent, a targeted therapy agent, an immunotherapy, or a combination thereof as described hereinabove.
  • a method for treating a cancer or other hyperproliferative disorder in a subject in need thereof comprising providing to said subject any one or more of compounds (20)-(23) as described hereinabove and a chemotherapeutic agent, a targeted therapy agent, an immunotherapy, or a combination thereof as described hereinabove.
  • a method for treating a cancer or other hyperproliferative disorder in a subject in need thereof comprising providing to said subject a compound represented by the structure of Formula (VI) as described hereinabove and a chemotherapeutic agent, a targeted therapy agent, an immunotherapy, or a combination thereof as described hereinabove.
  • a method for treating a cancer or other hyperproliferative disorder in a subject in need thereof comprising providing to said subject compounds (3) as described hereinabove and a chemotherapeutic agent, a targeted therapy agent, an immunotherapy, or a combination thereof as described hereinabove.
  • the present disclosure provides compositions comprising a targeted therapy agent, which, in one embodiment, is sorafenib.
  • a targeted therapy agent which, in one embodiment, is sorafenib.
  • a method for treating a cancer or other hyperproliferative disorder in a subject in need thereof comprising providing to said subject a compound represented by Formula (23): or a salt thereof; and (b) sorafenib or a salt thereof.
  • Compound of Formula (23) includes a compound represented by Formula (23),” “Compound 23,” and Compound (23) having all the same features and limitation. Without being bound to any specific theory or mechanism of action, it has been found that Compound (23) selectively modulates the interaction between voltage-dependent anion channel 1 (VDAC) and hexokinase enzyme (HK)-2. In some embodiments, Compound (23) prevents the binding of HK2 and VDAC thus inducing apoptosis.
  • VDAC voltage-dependent anion channel 1
  • HK hexokinase enzyme
  • Sorafenib which, in some embodiments, is “Nexavar” or “Sorafenib tosylate” interchangeably, having all the same features and limitations, is a kinase inhibitor drug used for treatment of renal cell carcinoma (RCC), hepatocellular carcinomas (HCC) and thyroid cancer, among others.
  • RCC renal cell carcinoma
  • HCC hepatocellular carcinomas
  • thyroid cancer among others.
  • sorafenib acts by inhibiting protein kinases, including VEGFR, PDGFR and RAF kinases. By blocking RAF kinases, sorafenib disrupts downstream signaling, preventing the activation of MEK and ERK, and hindering cancer cell proliferation. Further, inhibition of VEGFR and PDGFR interferes with signaling pathways that promote angiogenesis and tumor growth.
  • a method for increasing a sorafenib anti-tumor effect in a subject in need thereof comprising providing to said subject a compound represented by Formula (23): or a pharmaceutically acceptable salt thereof.
  • a method for synergistically increasing a sorafenib anti-tumor effect in a subject in need thereof comprising providing to said subject a compound represented by Formula (23): or a pharmaceutically acceptable salt thereof.
  • the effect of sorafenib is increased following administration of a compound represented by Formula (23).
  • the effect of sorafenib is increased by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100%, following administration of Compound (23).
  • the combination of Compound (23) and sorafenib induce a synergistic effect, i.e., the combination produces an effect that is greater than the sum of the separate effects of each component of the combination.
  • a pharmaceutical composition comprising a compound represented by Formula (23): and sorafenib, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable earner.
  • composition comprising Compound (23) and sorafenib is formulated for parenteral, oral, rectal, intranasal, topical, inhalation, intravenous, subcutaneous, intraperitoneal, intraarterial, transdermal, or intramuscular administration.
  • kits comprising a compound represented by Formula (23): and sorafenib, or pharmaceutically acceptable salts thereof, and instructions for use thereof.
  • compositions comprising Compound (23) and sorafenib.
  • a method for treating a cancer or other hyperproliferative disorder in a subject in need thereof comprising providing to said subject a compound represented by Formula (23): or a salt thereof; and (b) cisplatin or a salt thereof.
  • Compound of Formula (23) includes a compound represented by Formula (23),” “Compound 23,” and Compound (23) having all the same features and limitation. Without being bound to any specific theory or mechanism of action, it has been found that Compound (23) selectively modulates the interaction between voltage-dependent anion channel 1 (VDAC) and hexokinase enzyme (HK)-2. In some embodiments, Compound (23) prevents the binding of HK2 and VDAC thus inducing apoptosis.
  • VDAC voltage-dependent anion channel 1
  • HK hexokinase enzyme
  • cisplatin which in some embodiments might be also termed cisplatinum, platamin, neoplatin, cismaplat, cis-diamminedichloroplatinum(II) (CDDP) interchangeably, having all the same features and limitations, is a chemotherapy medication used to treat a number of cancers.
  • cisplatin is administered intravenously in normal saline for treatment of solid and haematological malignancies.
  • cisplatin may exert its effects by interfering with DNA replication, which kills the fastest proliferating cells, such as tumor cells.
  • a method for increasing a cisplatin anti-tumor effect in a subject in need thereof comprising providing to said subject a compound represented by Formula (23): or a pharmaceutically acceptable salt thereof.
  • a method for synergistically increasing a cisplatin anti-tumor effect in a subject in need thereof comprising providing to said subject a compound represented by Formula (23): or a pharmaceutically acceptable salt thereof.
  • the effect of cisplatin is increased following administration of a compound represented by Formula (23). In some embodiments, the effect of cisplatin is increased by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100%, following administration of Compound (23).
  • the combination of Compound (23) and cisplatin induces a synergistic effect, i.e., it produces a combined effect greater than the sum of the effects of the separate components of the combination.
  • composition comprising a compound represented by Formula (23):
  • a composition comprising Compound (23) and cisplatin is formulated for parenteral, oral, rectal, intranasal, topical, inhalation, intravenous, subcutaneous, intraperitoneal, intraarterial, transdermal, or intramuscular administration.
  • kits comprising a compound represented by Formula (23): and cisplatin, or pharmaceutically acceptable salts thereof, and instructions for use thereof.
  • compositions comprising Compound (23) and cisplatin.
  • compositions suitable for administration typically comprise the composition, for example the compound represented by Formula (23) and cisplatin, and a pharmaceutically acceptable carrier; or the compound represented by Formula (23) and sorafenib, and a pharmaceutically acceptable carrier.
  • the term “pharmaceutically acceptable carrier” is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Suitable carriers are described in the most recent edition of Remington’s Pharmaceutical Sciences, a standard reference text in the field, which is incorporated herein by reference. Preferred examples of such carriers or diluents include, but are not limited to, water, saline, ringer’s solutions, dextrose solution, and 5% human serum albumin. Liposomes and nonaqueous vehicles such as fixed oils may also be used. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.
  • compositions and formulations as described herein can be prepared by mixing the active ingredients having the desired degree of purity with one or more optional pharmaceutically acceptable carriers (Remington's Pharmaceutical Sciences 22 nd edition, 2012), in the form of lyophilized formulations or aqueous solutions.
  • Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed, and include, but are not limited to: buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arg
  • Zn- protein complexes Zn- protein complexes); and/or non- ionic surfactants such as polyethylene glycol (PEG).
  • exemplary pharmaceutically acceptable carriers herein further include insterstitial drug dispersion agents such as soluble neutral-active hyaluronidase glycoproteins (sHASEGP), for example, human soluble PH-20 hyaluronidase glycoproteins, such as rHuPH20 (HYLENEX®, Baxter International, Inc.).
  • sHASEGP soluble neutral-active hyaluronidase glycoproteins
  • rHuPH20 HYLENEX®, Baxter International, Inc.
  • a sHASEGP is combined with one or more additional glycosaminoglycanases such as chondroitinases.
  • the compounds of the invention are administered in the same pharmaceutical composition.
  • a compound represented by the structure of Formula (II) and a chemotherapeutic and/or a targeted therapy agent are administered in the same pharmaceutical composition.
  • a compound represented by the structure of Formula (23) and cisplatin are administered in the same pharmaceutical composition.
  • a compound represented by the structure of Formula (23) and sorafenib are administered in the same pharmaceutical composition.
  • the compounds of the invention are administered in separate pharmaceutical compositions.
  • a compound represented by the structure of Formula (II) and a chemotherapeutic and/or a targeted therapy agent are administered in separate pharmaceutical compositions.
  • a compound represented by the structure of Formula (23) and cisplatin are administered in separate pharmaceutical compositions.
  • a compound represented by the structure of Formula (23) and sorafenib are administered in separate pharmaceutical compositions.
  • the compounds of the invention are administered simultaneously.
  • a compound represented by the structure of Formula (II) and a chemotherapeutic and/or a targeted therapy agent are administered simultaneously.
  • a compound represented by the structure of Formula (23) and cisplatin are administered simultaneously.
  • a compound represented by the structure of Formula (23) and sorafenib are administered simultaneously.
  • the compounds of the invention are administered sequentially, in any order.
  • a compound represented by the structure of Formula (II) and a chemotherapeutic and/or a targeted therapy agent are administered sequentially, in any order.
  • a compound represented by the structure of Formula (23) and cisplatin are administered sequentially, in any order.
  • a compound represented by the structure of Formula (23) and sorafenib are administered sequentially, in any order.
  • a pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration.
  • routes of administration include parenteral, intravenous, intradermal, subcutaneous, oral, inhalation, transdermal, topical, intranasal, transmucosal, and rectal administration.
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS).
  • the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets.
  • the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules.
  • Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed.
  • Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
  • a suitable propellant e.g., a gas such as carbon dioxide, or a nebulizer.
  • Systemic administration can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art, and include, for example for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
  • Transmucosal administration can be accomplished using nasal sprays or suppositories.
  • the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.
  • the compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.
  • suppositories e.g., with conventional suppository bases such as cocoa butter and other glycerides
  • retention enemas for rectal delivery.
  • the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, poly glycolic acid, collagen, poly orthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
  • the materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.
  • Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the invention is dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.
  • compositions as described herein e.g. the composition of Formula (II), the composition of Formula (23), the chemotherapeutic and/or targeted therapy agent, cisplatin, and/or sorafenib are administered via parenteral administration.
  • the compositions as described herein e.g. the compositions as described herein, e.g. the composition of Formula (II), the composition of Formula (23), the chemotherapeutic and/or a targeted therapy agent, cisplatin, and/or sorafenib are administered via intravenous administration.
  • compositions as described herein e.g. the composition of Formula (II), the composition of Formula (23), the chemotherapeutic and/or a targeted therapy agent, cisplatin, and/or sorafenib are administered via rectal administration.
  • compositions as described herein e.g. the composition of Formula (II), the composition of Formula (23), the chemotherapeutic and/or a targeted therapy agent, cisplatin, and/or sorafenib are administered via intranasal administration.
  • compositions as described herein e.g. the composition of Formula (II), the composition of Formula (23), the chemotherapeutic and/or a targeted therapy agent, cisplatin, and/or sorafenib are administered via topical administration.
  • compositions of Formula (II), the composition of Formula (23), the chemotherapeutic and/or a targeted therapy agent, cisplatin, and/or sorafenib are administered via administration by inhalation.
  • the compositions are administered directly to the tumor site.
  • the administration comprises intratumoral injection, the implantation of a drug delivery device, or targeted drug-eluting nanoparticles.
  • formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as LipofectinTM), DNA conjugates, anhydrous absorption pastes, oil- in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. Any of the foregoing mixtures may be appropriate in treatments and therapies in accordance with the present invention, provided that the active ingredient in the formulation is not inactivated by the formulation and the formulation is physiologically compatible and tolerable with the route of administration.
  • a therapeutic regimen is carried out by identifying a subject, e g., a human patient suffering from (or at risk of developing) a malignancy, using standard methods. Efficaciousness of treatment is determined in association with any known method for cancer monitoring. Alleviation of one or more symptoms of the condition indicates a clinical benefit.
  • compositions of the invention are administered at intermittent dosing schedules or adaptive dosing regimens, allowing for flexibility in treatment based on the subject's response to therapy.
  • the compounds disclosed herein are administered with a sequential or phased administration strategy, in stages with defined intervals. This approach could be beneficial in managing side effects, optimizing treatment response, and potentially delaying or preventing the development of drug resistance.
  • the compounds disclosed herein are administered by continuous infusion techniques, thus allowing prolonged drug exposure. This continuous administration may be facilitated through implantable devices, wearable pumps, or other infusion systems, maintaining a consistent therapeutic drug concentration over an extended period.
  • a compound of Formula (II), a compound of Formula (23), a chemotherapeutic and/or a targeted therapy agent, cisplatin, and/or sorafenib are administered by a single route.
  • a compound of Formula (23), a chemotherapeutic and/or a targeted therapy agent, cisplatin, and/or sorafenib are administered by different routes .
  • a compound of Formula (23), a chemotherapeutic and/or a targeted therapy agent, cisplatin, and/or sorafenib are administered at different administration regimes. Kits
  • kits comprising (a) a compound represented by the structure of Formula (II) or a pharmaceutically acceptable salt thereof; and (b) a chemotherapeutic and/or a targeted therapy agent or a pharmaceutically acceptable salt thereof.
  • a kit comprising (a) compound of Formula (23) or a pharmaceutically acceptable salt thereof; and (b) a chemotherapeutic and/or a targeted therapy agent or a pharmaceutically acceptable salt thereof.
  • kits comprising (a) compound of Formula (23) or a pharmaceutically acceptable salt thereof; and (b) cisplatin or a pharmaceutically acceptable salt thereof.
  • a kit comprising (a) compound of Formula (23) or a pharmaceutically acceptable salt thereof; and (b) sorafenib or a pharmaceutically acceptable salt thereof.
  • the kit comprises bottles, vials, bags and syringes.
  • the compositions of Formula (II), the compound of Formula (23), the chemotherapeutic and/or targeted therapy agent, the cisplatin, or the sorafenib are provided in pre-filled syringes or containers for convenient and accurate dosage delivery.
  • the kit further comprises a package insert comprising instructions for using the composition.
  • the formulations in the kit are tailored for oral, injectable, or other appropriate routes of administration.
  • the container may be formed from a variety of materials such as glass, plastic (such as polyvinyl chloride or poly olefin), or metal alloy (such as stainless steel or hastelloy).
  • the kit may contain packaging features that enhance stability and shelf life of the drug. This may involve specialized packaging materials, storage conditions, or protective measures to preserve the integrity of the pharmaceutical composition. Additionally, the kit may include information regarding proper storage and handling.
  • the kit comprises means for monitoring the patient's response to the drug treatment, such as diagnostic tools, test kits, or instructions for regular check-ups.
  • This embodiment facilitates personalized medicine by tailoring the drug administration based on the patient's individual characteristics and response to therapy, thereby optimizing treatment outcomes.
  • the kit comprises drug formulations and administration methods or tools designed with specific patient populations in mind, thus tailoring drug formulations and administration methods to accommodate a specific medical need, as pediatric version or geriatric needs.
  • the article of manufacture or kit may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use.
  • the article of manufacture further includes one or more of another agent (e.g., a chemotherapeutic, a targeted therapy agent, and anti -neoplastic agent).
  • Suitable containers for the one or more agent include, for example, bottles, vials, bags and syringes.
  • Embodiments in the application that “comprise” a step or an element may, in other embodiments, “consist of’ the step or element, or in other embodiments, may “consist essentially of’ the step or element.
  • the term “consisting essentially of’ is to be interpreted to include the listed elements or steps, and any additional components or steps that do not affect the basic nature of the invention.
  • the term “consisting of’ is to be interpreted to include only the listed elements.
  • Words using the singular or plural number also include the plural or singular number, respectively.
  • a compound of Formula (23) can be represented as:
  • EXAMPLE 1 Compound (23) inhibition of viability and proliferation of liver cancer cells is dose-dependent
  • hepatocellular carcinoma cancer cell line HepG2 was used. Cells were added to wells (10,000/well) in BIOMIMESYS® 3D matrix formed by a crosslinking reaction of hydrosoluble modified hyaluronic acid and other matrix components with ADH (adipic acid dihydrazide) to mimic the extracellular matrix (ECM).
  • BIOMIMESYS® 3D matrix formed by a crosslinking reaction of hydrosoluble modified hyaluronic acid and other matrix components with ADH (adipic acid dihydrazide) to mimic the extracellular matrix (ECM).
  • EXAMPLE 2 Synergism of Compound (23) and targeted therapy anti-cancer drugs
  • Cisplatin had a ECso of 100 pM for cell viability (Table 4), and Compound (23) had a ECso of 300 nM for cell viability (Table 5).
  • Compound (23) represents a breakthrough technology that uniquely interferes with the binding of hexokinase 2 to the VDAC1 mitochondrial channel in cancer cells without affecting hexokinase 1 in normal cells. This allows cancer-specific treatment that is both effective and safe. Moreover Compound (23) reduces the formation of Lactate in the tumor microenvironment.
  • a chemotherapy drug cisplatin
  • a targeted therapy drug Sorafenib
  • mice were treated with cisplatin twice a week, and/or with Compound (23) daily.
  • the doses and routes of administration for each therapeutic are detailed in Table 7.
  • body weight, behaviour, and clinical signs were evaluated every two days, and food and water consumption were monitored and recorded. An animal was sacrificed once its tumor grew to 1,800mm 2 or greater or once it lost >20% of its body weight.
  • Tumor growth (without administration of the therapeutic compounds), Tumor Growth Inhibition (TGI%) as a result of administration of compounds, and the survival curve were calculated for each treatment group.
  • TGI Tumor Growth Inhibition
  • the tumor was removed from each animal and fixated in formalin. Aliquots were retained for further tests, which will include analysis of the amount and activity of markers of infiltrated immune cells (Neutrophils, NK, CD4 and CD8 T-cells, etc). The ratio of CD4 T effector/Treg, as well as macrophages and their Ml and M2 markers, concentration of lactate in the tumor, and the tumor micro-environment will also be analysed.
  • Tumor size is presented in Figure 3 through day 22 of treatment, which was the first day that mice in the control untreated mice group died. Data from cisplatin at 1 mg/kg alone, Compound (23) alone, 1 mg/kg cisplatin + Compound (23), and the control untreated group is presented. The group of mice treated with the combination treatment of cisplatin (1 mg/kg) and Compound (23) (400 mg/kg) had the strongest inhibition of tumor expansion (Figure 3), with a 35.1% inhibition of tumor growth (TGI). Treatment of animals with Compound (23) alone inhibited tumor growth more effectively than treatment with cisplatin alone. Cisplatin treatment alone at the lower dose of 0.5 mg/kg demonstrated minor effects at day 22 (data not shown). Effectiveness of treatments compared to control groups for TGI
  • mice with a combination of cisplatin (1 mg/kg) and Compound (23) (400 mg/kg) had a greater effect on tumor reduction than the sum of the effects of each drug administered alone (Table 8, right hand column) after 19, 38 and 47 days of treatment.
  • a survival curve reveals the strong effect of the combined treatment with 1 mg/kg of cisplatin with 400 mg/kg of Compound (23), relative to control untreated group ( Figure 5).
  • the control group has a median survival of 26 days, while the cisplatin 1 mg/kg with Compound (23) treated group had a median survival of 45 days, which represents a more than 70% elongation of median survival.
  • These data provide evidence in an in vivo model that combination treatment increases survival of subjects and also indicates that the treatment will have fewer adverse side effects than existing treatments, because a lower dosage of cisplatin (1 mg/kg) is needed when combined with Compound (23).
  • the group treated with 1 mg/kg dosage of cisplatin as a monotherapy had a median survival of only 31 days, compared to 45 days for the combination treatment.

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Abstract

La présente invention concerne des polythérapies pour le traitement du cancer, lesdites thérapies comprenant un dérivé de pipérazine et un agent de thérapie chimiothérapeutique et/ou ciblé, des procédés pour leur préparation, des compositions pharmaceutiques comprenant de tels composés, et des procédés d'utilisation de ces composés, en particulier pour la thérapie ciblée de troubles hyperprolifératifs, y compris des troubles hyperprolifératifs bénins, des cancers et des états pré-cancéreux.
PCT/IL2025/050092 2024-01-30 2025-01-26 Thérapies synergiques pour le traitement du cancer Pending WO2025163633A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018033918A1 (fr) * 2016-08-18 2018-02-22 Vidac Pharma Ltd. Dérivés de pipérazine, compositions pharmaceutiques et leurs procédés d'utilisation
WO2018083704A1 (fr) * 2016-11-07 2018-05-11 Vidac Pharma Ltd. Utilisation de composés de séparation mitochondrie/hexokinase 2 pour activer des réponses immunitaires
WO2018083705A1 (fr) * 2016-11-07 2018-05-11 Vidac Pharma Ltd. Utilisation de composés de détachement d'hexokinase 2/mitochondries pour le traitement de cancers exprimant l'hexokinase 2 (hk2)

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018033918A1 (fr) * 2016-08-18 2018-02-22 Vidac Pharma Ltd. Dérivés de pipérazine, compositions pharmaceutiques et leurs procédés d'utilisation
WO2018083704A1 (fr) * 2016-11-07 2018-05-11 Vidac Pharma Ltd. Utilisation de composés de séparation mitochondrie/hexokinase 2 pour activer des réponses immunitaires
WO2018083705A1 (fr) * 2016-11-07 2018-05-11 Vidac Pharma Ltd. Utilisation de composés de détachement d'hexokinase 2/mitochondries pour le traitement de cancers exprimant l'hexokinase 2 (hk2)

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