[go: up one dir, main page]

WO2024105699A1 - Composition pour le traitement du cancer du sein résistant au paclitaxel et son procédé de préparation - Google Patents

Composition pour le traitement du cancer du sein résistant au paclitaxel et son procédé de préparation Download PDF

Info

Publication number
WO2024105699A1
WO2024105699A1 PCT/IN2023/051065 IN2023051065W WO2024105699A1 WO 2024105699 A1 WO2024105699 A1 WO 2024105699A1 IN 2023051065 W IN2023051065 W IN 2023051065W WO 2024105699 A1 WO2024105699 A1 WO 2024105699A1
Authority
WO
WIPO (PCT)
Prior art keywords
paclitaxel
iiim
cells
cscs
breast cancer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IN2023/051065
Other languages
English (en)
Inventor
Sameer Ahmad MIR
Shahnawaz Khan
Sameer Ullah KHAN
Masroor Ahmad PADDAR
Loveleena Kaur ANAND
Mir Shahid MAQBOOL
Atul Kumar
Anil PADALA
Gousia CHASHOO
Utpal Nandi
Gurdarshan Singh
Bhahwal Ali Shah
Qazi Naveed AHMED
Fayaz Malik
Baseerat HAMZA
Kaneez FATIM
Nadiem NAZIR
Ashish DOGRA
Amit Kumar
Govind Yadav
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Council of Scientific and Industrial Research CSIR
Original Assignee
Council of Scientific and Industrial Research CSIR
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Council of Scientific and Industrial Research CSIR filed Critical Council of Scientific and Industrial Research CSIR
Priority to AU2023380432A priority Critical patent/AU2023380432A1/en
Priority to EP23891051.7A priority patent/EP4601643A1/fr
Publication of WO2024105699A1 publication Critical patent/WO2024105699A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids

Definitions

  • the present invention relates to a composition for treating paclitaxel-resistant breast cancers.
  • the composition comprises Paclitaxel and IIIM-152 in the effective range of the ratio of 1:5 to 1:10 along with suitable additives.
  • the present invention also relates to the method for preparing the composition comprising Paclitaxel and IIIM-152.
  • Triple-negative breast cancer a special subtype of breast cancer with distinct clinical features, has a poorer prognosis and is characterized by larger tumor volume, a higher degree of proliferation, early risk of relapse, prevalence of visceral and metastatic progression, and aggressive behaviour.
  • Gene expression analysis has shown that nearly 70% of all TNBC tumors are basal-like and thus initially TNBCs were often used as surrogates for basal-like breast cancer due to the absence of ER, PR, and Her2 but a substantial number of basal-like tumors express ER / PR or HER2 and at least one other basal molecular marker, mainly cytokeratin 5 and 6 (CK5/6), CK14, CK17, caveolin 1/2, and EGF receptor (EGFR).
  • CK5/6 cytokeratin 5 and 6
  • CK14 CK14
  • CK17 caveolin 1/2
  • EGF receptor EGF receptor
  • TNBCs are usually ductal or medullary or invasive or metaplastic and grade III tumors with elevated mitotic rates and p53 mutations. It is more common in younger women and is correlated with BRCA-1 mutation in general. TNBC cells spread from the local site to the bones, lungs, liver, and brain where the survival rate declines from 90 to 20%. TNBC is itself biologically heterogeneous and is further sub-classified into seven subclasses based primarily on comprehensive gene expression profile and prediction analysis of microarray-50 (PAM50) classifier- Basal-like-l(21%), Immunomodulatory (23%), Mesenchymal (20%), Basal-like-2 (8%), Mesenchymal stem-like (10%), Luminal androgen receptor (1%), and Unstable (17%).
  • PAM50 microarray-50
  • TNBCs constitute a distinct histopathological category and therefore pose a major challenge for the diagnosis and treatment of aggressive breast cancers. Therefore, the main aim of Triple-Negative Breast Cancer investigators is to define the prognostic factors or targets that can be useful for the treatment of this particular tumor subtype. While advanced therapies exist, the prognosis for this advanced stage is poor. Chemotherapy is the sole treatment option for TNBC management owing to the absence of precise targets and acquired resistance to available radio and chemo agents is huge clinical challenge. Current Treatment options in TNBC and the need for new agents:
  • chemotherapeutic s such as paclitaxel, cisplatin, cyclophosphamide, doxorubicin, fluorouracil, etc, target conventional mechanisms of TNBC. Besides these, irinotecan, trabectedin, and ABI-007 were also seen effective in TNBCs.
  • preclinical and clinical trials involving inhibition of poly-ADP ribose polymerase (PARP) enzymes with PARP inhibitors such as Iniparib and Olaparib have shown some potential in early trials, which was further augmented when provided in combination with gemcitabine and carboplatin.
  • PARP poly-ADP ribose polymerase
  • the monoclonal antibody cetuximab is also used to combat TNBC.
  • Erlotinib and lapatinib have also been used against TNBC.
  • TNBC tyrosine-kinase inhibitors
  • pCR pathologic complete response
  • TNBCs are commonly considered to be more aggressive than that other subtypes and therefore undergo increased glycolysis, metformin demonstrated impressive results by induction of AMP-activated protein kinase.
  • RR paclitaxel enhanced response rate
  • Other angiogenic inhibitors Avastin and Docetaxel (A VADO) lowered the risk by 47%.
  • cisplatin had a higher degree of pathological complete response (pCR).
  • pCR pathological complete response
  • a bevacizumab neoadjuvant combination with cisplatin exhibited 15% of pCR.
  • epirubicin or 5-FU cisplatin showed a response rate of 40%.
  • chemoresistance and lack of responsiveness to chemotherapies are responsible for 90% of drug failures.
  • Claim of this invention is based on Current Clinical Challenges and Shortcoming of available treatment options:
  • cancer stem cells CSCs
  • CSCs cancer stem cells
  • CSCs Cancer Stem Cells
  • Cancer stem cells also known as tumor-initiating cells (TICs) are characterized as a subpopulation of self-renewing cancer cells that possess a strong tumorigenic capacity and can undergo multilineage differentiation to produce all forms of malignant cells.
  • CSCs accelerate tumor development and are known to be a source of tumor relapse and disease progression, possibly by their therapy resistance and metastatic ability.
  • cancer cannot be fully treated in its late stages. While chemotherapeutic agents currently used can reduce tumor mass, recurrence is normal. Therefore, CSCs are being investigated widely in multiple cancers.
  • CSCs are involved in metastatic breast cancer development. This is particularly important considering that the majority of deaths from cancer are attributed to secondary lesions that have spread from the primary tumor.
  • Immunohistochemistry of breast cancer cells collected from the bone marrow utilizing the CD44highCD24-/low phenotype indicates that metastatic tumors had a significantly higher proportion of CSCs relative to the primary site.
  • CSCs isolated by ALDH activity has been shown to mediate metastasis in both in vitro and xenograft studies of inflammatory breast cancer (IBC) models.
  • IBC inflammatory breast cancer
  • the presence of ALDH+ cells in tumors in IBC patients was associated with both early metastasis onset and reduced overall survival.
  • CSCs were also suggested to modify the structure of the tissue by inducing epithelial remodeling. This disturbance of normal tissue structure may be another mechanism by which CSCs may lead to metastasis. Therapy resistance and tumor recurrence
  • a possible mechanism for understanding the recurrence of breast cancer is the resistance of CSCs to chemo therapy/radiotherapy.
  • the CSCs population is enriched during neoadjuvant chemotherapy, indicating that CSCs are more resistant than the bulk of the tumor.
  • Treatment with chemotherapeutic medications paclitaxel or 5-fluorouracil
  • SUM159 and SUM149 cells contributed to enrichment in the percentage of stem-like cells.
  • the association between EMT and CSCs is also applicable to therapeutic resistance, as cells undergoing EMT are more chemotherapeutic resistant.
  • Cells derived from tumors with Her2-antigen dysfunction undergoing EMT had upregulated protein pump expression (BCRP and PGP) associated with drug resistance. These cells were thus protected from mitoxantrone and etoposide pharmacological treatments.
  • the mesenchymal tumor cells also had elevated levels of DNA repair enzyme and were resilient to ionizing radiation.
  • Differentiation therapy is another strategy for targeting specifically CSCs.
  • CSCs are usually locked into an undifferentiated state, their capacity for self-renewal and their differentiation potential render them extremely tumorigenic. Therefore, eliminating this blockade and pushing them back into differentiated constantly dividing cells could eradicate them in conjunction with chemotherapy and thus minimize the risk of tumor relapse.
  • ATRA all-trans retinoic acid
  • CSCs In the case of CSCs, this strategy will cause their exit from the CSC state into the more differentiated or epithelial state (126).
  • CSCs lack markers of differentiation. For example, breast, colon, and prostate CSCs lack epithelial differentiation markers cytokeratin, whereas glioblastoma CSCs lack glial fibrillary acidic protein.
  • CSC differentiation can be an effective clinical strategy, since the bulk of the tumor has less potential for proliferation and is more responsive to chemotherapy or radiation therapy.
  • Potential way-out that induce quiescent CSCs to transform into more mature tumor cells involve stimulation of various signalling pathways, such as morphogen-driven signalling cascades, modifying gene expression profiles with microRNAs, and epigenetic differentiation therapy.
  • Piccirillo et al. for example, used BMP signalling to cause differentiation of CSCs in models of human brain cancer.
  • administration of BMP4 to glioblastoma cultures in vitro or to human brain cancer in vivo has resulted in differentiation of glioblastomas and substantially decreased the number of CD133 + cells.
  • CSCs Paclitaxel Resistant Cancer Stem Cells
  • imidazoles and imidazole-based derivatives have been evaluated in various cancers. For instance, imidazole-based molecules inhibited tumor growth in a panel of the National Cancer Institute's 60 human cancer cell lines. Remarkable cytotoxic activities were shown against various cell lines by a novel series of imidazoles. The trisubstituted- imidazoles decreased the expression of cyclin DI and increased the cleavage of PARP. Furthermore, imidazoles have been reported to act against tumor resistance and relapse.
  • Another strategy is to use cell makers such as CD44+CD24-/lowlin- and ALDH positive to differentiate mammary stem/progenitor cells from differentiated cancer cells. It has been documented that as fewer as 500 ALDH-positive cells could develop breast tumors in less than 40 days, while 50,000 ALDH-negative cells did not generate a breast tumor. ALDH-positive cells and CD44+CD24-/lowlin- have been reported as narrow overlaps with the greatest tumorigenic potential, developing tumors from as minimal as 20 cells. In comparison, ALDH-positive cells without the CD44+CD24-/lowlin- marker have been able to develop tumors from 1,500 cells, whereas 50,000 CD44+CD24-/lowlin- negative cells have not.
  • IIIM-152 we used the Aldefluor Assay to assess the potential of IIIM-152 to target stem/progenitor cells of TNBCs.
  • IIIM-152 could suppress cancerinitiating ALDH-positive cells in vitro by 63% to 90% in MDA-MB-231 and SUM159 cells respectively.
  • IIIM-152 concentrations inhibiting stem/progenitor cells in both the mammosphere assay and the CD44+/CD24- Aldefluor assays had only marginal effects on the bulk population of breast cancer cell lines, which suggests selective targeting of stem/progenitor cells by IIIM-152.
  • IIIM-152 was able to take down breast CSCs in vivo.
  • Intravenous injection of IIIM-152 for 2 weeks decreased tumor volume in primary BALB/c mice and the population of ALDH-positive cell population of the tumor by 50%.
  • IIIM-152 has many advantages as a chemoprevention agent, such as excellent bioavailability and minimal toxicity.
  • the IIIM-152 pharmacokinetics was conducted by intravenous (IV) and oral (PO) routes at a 50 mg/kg dose.
  • the mean plasma clearance (Cl) was found to be high (0.59L/h/kg) with an elimination half-life (tl/2) of 5.7h.
  • the volume of distribution at a steady-state was reported to be 8.7 L/kg and the Mean plasma concentration (AUClast) was found to be 27492 ng. h/mL.
  • the median time to reach the maximum plasma concentration was discovered to be 11.4h with an initial plasma concentration (Co) of 7256 ng/mL.
  • the volume of distribution at a steady-state was reported at 2.1 1/kg and the Plasma exposure (AUClast) was found to be 32310 ng.h/mL.
  • AUClast Plasma exposure
  • no mortality and signs of toxicity such as loss of body weight, food consumption, relative organ weight, or gross pathology of vital organs during treatment with different doses as compared with control in the toxicity study.
  • IIIM-152 was also found to be safe up to the dose of 200 mg/kg in 14 days of repeated-dose studies in mice.
  • Imidazole compounds were shown to interfere with the Wnt/p-Catenin self-renewal pathway in Triple-Negative Breast Cancer. Jeong et al. previously reported that imidazole increased the inhibitory phosphorylation and subsequent degradation of P-catenin in melanoma. In consistent with this study, we revealed that IIIM-152 was able to down-regulate the Wnt/p- catenin self-renewal pathway in TNBCs, and IIIM-152-induced P-catenin phosphorylation and (Ser33/Ser37/Thr41) and proteasome degradation was likely through GSK3P activation.
  • IIIM-152 was able to target breast CSCs as evaluated by the mammosphere formation assay, Aldefluor assay, CD44+24- assay, and tumor growth upon 4T1 implantation in BALB/C mice. Furthermore, our research reported the downregulation of the Wnt/p-catenin self-renewal pathway by IIIM-152 as one of the plausible mechanisms for its efficacy. All these findings endorse the use of IIIM-152 for chemoprevention against breast cancer. These findings provide a convincing rationale for preclinical and clinical assessment of IIIM-152 for breast cancer therapies.
  • An objective of the present invention is to provide a combitorial treatment of Paclitaxel and IIIM152 used in the effective ratio in the rage of 1:5 to 1: 10, for eliminating Paclitaxel nonresponsive (resistant) Triple Negative Breast Cancer Stem Cells (CSCs).
  • CSCs Paclitaxel nonresponsive (resistant) Triple Negative Breast Cancer Stem Cells
  • Another objective of the present invention is to provide a method for preparation of composition comprising Paclitaxel and IIIM152.
  • an objective of the present invention is to provide a method for treating Paclitaxel resistant Cancer Stem Cells in TNBCs by combination of Paclitaxel and IIIM152.
  • Yet another objective of the present invention is to provide use of combination of Paclitaxel and IIIM152 for treatment of Paclitaxel resistant Cancer Stem Cells in TNBCs.
  • the present invention provides a novel combination of Paclitaxel and IIIM152 when used at the ratio in the range of the range of 1-5 : 1-10, was found effective against Paclitaxel resistant Cancer Stem Cells in TNBCs.
  • the present invention also provides a method for preparation of composition comprising Paclitaxel and IIIM152.
  • IIIM152 showed encouraging PKPD profile.
  • Fig 1 shows the general structure of representative of compounds referred to in Table 1 and Table 2.
  • the present invention relates to a composition for treating paclitaxel-resistant breast cancers. These derivatives show to be useful against Paclitaxel-resistant triple-negative breast cancer and in combination showed efficacy against drug-resistant CSCs.
  • composition for treating paclitaxel-resistant triple negative breast cancer consisting of Paclitaxel and IIIM-152 in the ratio in the range of 1-5: 1-10.
  • it provides a method for preparing the composition comprising: a) Providing Paclitaxel b) Providing IIIM152 c) Dissolving DMSO (1 part) + Tween-80 (1 Part) and 0.9% Normal Saline (8 parts) making final composition as 1:1:8 to get a buffer solution. d) Dissolving paclitaxel and IIIM152 in the buffer solution to obtain the composition.
  • Yet another embodiment of the invention provides a method of treatment of paclitaxel- resistant triple negative breast cancer by using combination of of Paclitaxel and IIIM-152 in the ratio in the range of 1-5: 1-10. Further an embodiment of the invention provides use of combination of Paclitaxel and IIIM- 152 in the ratio in the range of 1-5: 1-10 for treating paclitaxel-resistant triple negative breast cancer.
  • MDA-MB-231, SUM159, and 4T1 mouse mammary carcinoma cell lines were purchased from American Type Culture Collection(ATCC). Both MDA-MB-231 and SUM 159 cell lines are negative for estrogen receptor (ER), and progesterone receptor (PR) and does not have Her2 overexpression. MDA-MB-231 and 4T1 were maintained in RPMI 1640(Invitrogen) supplemented with 10% fetal bovine serum (Thermo Fisher Scientific).
  • SUM159 was maintained in Ham’s F12 medium (Invitrogen) supplemented with 5% fetal bovine serum, 1% antibiotic-antimycotic (Gibco), 5pg/mE insulin (Gibco), Ipg/mE hydrocortisone (Sigma- Aldrich).
  • PTEN and P53 knockdown MCF10A cell lines were established by transduction with shRNA lentiviral particles purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA). Cells were grown in a CO2 incubator (Thermocon Electron Corporation, USA) at 37oC in an atmosphere of 95% air and 5% CO2 with 98% humidity. Different molecules were dissolved in DMSO and were delivered to cell cultures in a complete medium.
  • Propidium Iodide and paclitaxel were purchased from Invitrogen. LiCl was purchased from Fisher Scientific and MG 132 from TOCRIS Bioscience.
  • Antibodies against oct4, sox2, cyclin DI, P-catenin, phospho-b-catenin ser33/ser37/Thr41, phospho-GSK3P ser9, E-cadherin, Vimentin, Zebl, ATG5, and p62 were purchased from cell signalling technology.
  • Antibodies against snail and LC3 II were purchased from Sigma Aldrich.
  • IIIM-152 inhibits proliferation and induces cell cycle inhibition of triple-negative breast cancer cells in an apoptosis-independent manner.
  • IIIM-152 The antiproliferative effect of IIIM-152 was measured by SRB assay on triple-negative breast cancer cell lines MDA-MB-231 and SUM159. MDA-MB-231 and SUM159 cells were treated with different concentrations of IIIM-152 for a time period of 24-96 hours. IIIM-152 proved to be a non-toxic compound and exhibited higher IC50 values of more than lOOpM even when cells were treated for longer time periods spanning up to 96 hours.
  • IIIM-152 inhibited proliferation and induced Gl-phase cell cycle arrest in triple-negative breast cancer cells (1C)IIIM-152 was found to arrest the cells in the Go/Gl phase of the cell cycle, which was also confirmed by a drastic decrease of cyclin DI expression using western blot analysis.
  • Table 1A IC50 values of IIIM-152 against TNBC cell lines
  • Table IB Cell Cycle Inhibitory potential of IIIM-152 in TNBC cell lines
  • HIM- 152 effectively inhibits the growth of breast cancer stem/progenitor cells in vitro and attenuates paclitaxel-induced augmentation of the Stem cell population in TNBCs. It has been shown that in breast carcinomas, a cell population with high ALDH activity, high CD44+/24- expression, and ability to form mammospheres is capable of enriching tumorigenic stem/progenitor cells. This sub-population of cells has been attributed to be responsible for breast cancer progression, tumor relapse and chemotherapeutic resistance. IIIM-152 was shown to reduce the number of ALDH+ expressing cells, CD44+/24- expression besides decreasing the number and size of mammospheres formed in
  • MDA-MB-231 and SUM159 cells in both time and dose-dependent manner.
  • IIIM-152 inhibits breast cancer stem/progenitor cells at the concentration (10-80pmol/l) without affecting the bulk population of cancer cells, thus implying that IIIM-152 preferentially targets cancer stem cells compared to bulk cancer cells.
  • IIIM- 152 eliminates paclitaxel resistant mammospheres at combination of Paclitaxel (lOnM) and IIIM152 (40pM) Table -2D IIIM-152 effectively effects growth of breast cancer stem progenitor cells
  • IIIM-152 suppresses Epithelial-mesenchymal transition (EMT) in triple negative breast cancer cells.
  • IIIM-152 suppresses Epithelial-mesenchymal transition (EMT) in triple negative breast cancer cells
  • IIIM-152 reduces breast cancer stem/progenitor cells in vivo.
  • IIIM-152 could reduce breast CSCs in vivo
  • 4T1 Balb/c mouse mammary carcinoma model 4T1 cells were injected in mammary fat pad and after two weeks animals were injected on alternate days with 50mg/kg of IIIM-152. Treatment with compound continued for 2 weeks, we found 50% inhibition in tumor volume compared to 0.9% NaCl solution control group. Moreover, IIIM-152 had no apparent toxicity as animals remained healthy throughout the experiment and no body weight loss was observed.
  • Table -4A HIM 152 significantly decreased the tumor volume in BALb/c mice
  • IIIM-152 Since novel compounds have to be explored for their pharmacokinetic behaviour, which is one of the essential components of the drug discovery and development process.
  • IIIM-152 we have administered IIIM-152 in mice via oral and i.v routes followed by a collection of blood through retro-orbital plexus and the plasma concentration was determined by LC-MS/MS system (Model name). Plasma concentrations at different time points along with the pharmacokinetic parameters are given in Table.
  • the pharmacokinetic analysis of IIIM 152 was based on plasma concentration versus time profile analysis using non-compartmental methods.
  • the primary pharmacokinetic parameters used to assess dose proportionalities were the area under the curve (AUCO-t) and maximum plasma concentration (Cmax).
  • IIIM-152 was well absorbed following oral administration with a T max and C max of 30 min and 13836 ng/ml respectively after an oral dose of 40 mg/kg. Further, AUCO-infinity, after oral administration was 104085 ng/h/ml, and the AUCO-t, was 93309 ng h/ml. On the other hand, IIIM 152 showed shorter half (15 min) when administered intravenously with a high clearance rate i.e 15.46 L/h/kg. Following intravenous administration at a dose of 20 mg/kg, AUCO-t and AUC0-co obtained were 550.6 and 576.5 ng/ml, respectively.
  • IIIM-017 also displayed a higher volume of distribution of 8.7 L/kg and a medium clearance of 0.59 L/h/kg.
  • the oral bioavailability of IIIM-152 w.r.t i.v administration in male BALB/c mice was found to be approximately 90%.
  • IIIM-152 exhibited a promising pharmacokinetic profile and excellent oral bioavailability.
  • the Wnt/b-catenin pathway is mainly responsible for maintaining stem cell self-renewal and is mostly dysregulated in triple-negative breast cancers. Since Cyclin DI is a direct downstream target of P-catenin and is required for progression through the G1 phase of the cell cycle. As we observed that IIIM-152 downregulated cyclin DI and arrested cells in the G1 phase of the cell cycle in MDA-MB-231 and SUM159 cells. This prompted us to check whether downstream targets of wnt/p-catenin are downregulated by IIIM-152.
  • IIIM-152 significantly decreased the expression levels of P-catenin and cyclin DI besides decreasing the phosphorylation of GSK3P at ser9 increasing the activity of GSK3P, thereby destabilizing P-catenin.
  • Proteasome inhibitor MG132 was also used to confirm the increased expression levels of phosphorylated P-catenin at Ser33/Ser37/Thr41 by GSK3p. GSK3b phosphorylation of P- catenin at ser33/ser37/Thr41 renders it to ubiquitin-mediated proteasome degradation.
  • Table 6A IIIM-152 significantly decreased the expression levels of p-catenin and cyclin
  • Fig 6C- IIIM-152 neutralizes the effect of activation of Catenin by LiCl.
  • IIIM 152 is a Non-toxic molecule with a promising Pharmacokinetic Profile.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Le composé IIIM-152 et ses dérivés ont été rapportés en tant que modulateurs de cellules souches puissants par régulation à la baisse de la signalisation de la bêta-caténine. Les TNBC sont des cancers très agressifs et la chimiothérapie reste l'une des options thérapeutiques primaires. Cependant, les CSC restent insensibles au traitement par Paclitaxel, ce qui entraîne une récidive de la maladie et la formation de métastases, et constitue l'un des défis cliniques majeurs. Le traitement combiné par IIIM élimine les cellules souches cancéreuses résistantes au Paclitaxel, tandis que le traitement par Paclitaxel en monothérapie est incapable de cibler la sous-population de CSC. De même, une combinaison de Paclitaxel-IIIM152 a montré une réduction significative de la charge tumorale et une diminution du nombre de CSC dans des tumeurs excisées. La combinaison de IIIM-152 et de Paclitaxel s'avère cliniquement efficace dans le traitement des cellules souches cancéreuses résiduelles hautement agressives insensibles au Paclitaxel pour obtenir un traitement durable. L'invention concerne également un procédé de préparation de la composition comprenant du Paclitaxel et du IIIM-152.
PCT/IN2023/051065 2022-11-18 2023-11-17 Composition pour le traitement du cancer du sein résistant au paclitaxel et son procédé de préparation Ceased WO2024105699A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2023380432A AU2023380432A1 (en) 2022-11-18 2023-11-17 Composition for treating paclitaxel-resistant breast cancer and method for preparation thereof
EP23891051.7A EP4601643A1 (fr) 2022-11-18 2023-11-17 Composition pour le traitement du cancer du sein résistant au paclitaxel et son procédé de préparation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN202211066609 2022-11-18
IN202211066609 2022-11-18

Publications (1)

Publication Number Publication Date
WO2024105699A1 true WO2024105699A1 (fr) 2024-05-23

Family

ID=91083931

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2023/051065 Ceased WO2024105699A1 (fr) 2022-11-18 2023-11-17 Composition pour le traitement du cancer du sein résistant au paclitaxel et son procédé de préparation

Country Status (3)

Country Link
EP (1) EP4601643A1 (fr)
AU (1) AU2023380432A1 (fr)
WO (1) WO2024105699A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100297075A1 (en) * 2009-02-12 2010-11-25 Arqule, Inc. Combinational compositions and methods for treatment of cancer
WO2013085902A1 (fr) * 2011-12-05 2013-06-13 The University Of Texas M.D. Procédés de polythérapie pour le traitement d'un cancer du sein inflammatoire
EP2959918A1 (fr) * 2014-05-15 2015-12-30 J-Pharma Co., Ltd. Composition d'agent anti-tumeur maligne

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100297075A1 (en) * 2009-02-12 2010-11-25 Arqule, Inc. Combinational compositions and methods for treatment of cancer
WO2013085902A1 (fr) * 2011-12-05 2013-06-13 The University Of Texas M.D. Procédés de polythérapie pour le traitement d'un cancer du sein inflammatoire
EP2959918A1 (fr) * 2014-05-15 2015-12-30 J-Pharma Co., Ltd. Composition d'agent anti-tumeur maligne

Also Published As

Publication number Publication date
EP4601643A1 (fr) 2025-08-20
AU2023380432A1 (en) 2025-05-29

Similar Documents

Publication Publication Date Title
US11964941B2 (en) 5-Bromo-indirubins
US9073851B2 (en) Compositions and methods for treating cancer
Son et al. Targeted therapy of cancer stem cells: Inhibition of mTOR in pre-clinical and clinical research
US20220274964A1 (en) 5-bromo-indirubins
EP3802544A1 (fr) Composés de pyrazolo-pyrimidin-amino-cycloalkyle et leurs utilisations thérapeutiques
US9512138B2 (en) Compositions and methods for treating cancer
CA3163095A1 (fr) Polytherapie impliquant des composes macrocycliques de diaryle
EP3858836A1 (fr) Composé et utilisation associée
EP3012248B1 (fr) Substance possédant une activité inhibitrice des tyrosine kinases, son procédé de préparation et son utilisation
Carrasco et al. Meroxest improves the prognosis of immunocompetent C57BL/6 mice with allografts of E0771 mouse breast tumor cells
EP4601643A1 (fr) Composition pour le traitement du cancer du sein résistant au paclitaxel et son procédé de préparation
CN106389437A (zh) 低剂量西地那非作为抗肿瘤药物的应用
JP2011514355A (ja) 肺癌、腺癌及び他の病状のための治療方法及び組成物
US10512630B2 (en) Compositions and methods for treating cancer
CN115461054A (zh) 延伸因子1-α抑制剂及其用途
JP2021525809A (ja) プロドラッグおよびその医学的使用
CN106333951B (zh) 一种mTOR激酶抑制剂与MAPK激酶抑制剂的组合物的应用
WO2017087818A1 (fr) Double inhibiteur de kinase p38/src et leur utilisation comme agents thérapeutiques
CN112168828A (zh) 一种egfr与cdk4/6小分子靶向药组合物及其应用
CA2700664A1 (fr) Therapies pour le traitement de cancer au moyen de melanges d'inhibiteurs de la cox-2 et d'inhibiteurs d'aromatase ou de melanges d'inhibiteurs de la cox-2 et d'antagonistes du recepteur d'oestrogene

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23891051

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2023891051

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: AU2023380432

Country of ref document: AU

ENP Entry into the national phase

Ref document number: 2023891051

Country of ref document: EP

Effective date: 20250514

ENP Entry into the national phase

Ref document number: 2023380432

Country of ref document: AU

Date of ref document: 20231117

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

WWP Wipo information: published in national office

Ref document number: 2023891051

Country of ref document: EP