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WO2025232723A1 - Méthode de traitement avec un inhibiteur de kinase d'adhérence focale - Google Patents

Méthode de traitement avec un inhibiteur de kinase d'adhérence focale

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Publication number
WO2025232723A1
WO2025232723A1 PCT/CN2025/092841 CN2025092841W WO2025232723A1 WO 2025232723 A1 WO2025232723 A1 WO 2025232723A1 CN 2025092841 W CN2025092841 W CN 2025092841W WO 2025232723 A1 WO2025232723 A1 WO 2025232723A1
Authority
WO
WIPO (PCT)
Prior art keywords
day
chemotherapy agent
administered
pharmaceutically acceptable
compound
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.)
Pending
Application number
PCT/CN2025/092841
Other languages
English (en)
Inventor
Zhou Yu
Yifan Zhai
Dajun Yang
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.)
Ascentage Pharma Suzhou Co Ltd
Ascentage Pharma Group Co Ltd
Original Assignee
Ascentage Pharma Suzhou Co Ltd
Ascentage Pharma Group Co Ltd
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 Ascentage Pharma Suzhou Co Ltd, Ascentage Pharma Group Co Ltd filed Critical Ascentage Pharma Suzhou Co Ltd
Publication of WO2025232723A1 publication Critical patent/WO2025232723A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to a method of treating cancer, especially small-cell lung cancer.
  • the method further involves the administration of a focal adhesion kinase inhibitor (e.g. compound A disclosed herein) .
  • the method further involves the co-administration of a focal adhesion kinase inhibitor and a chemotherapy agent (e.g. topotecan, etoposide, and carboplatin. )
  • a focal adhesion kinase inhibitor e.g. compound A disclosed herein
  • a chemotherapy agent e.g. topotecan, etoposide, and carboplatin.
  • Lung cancer is one of the most common malignant tumors in the world, and it is the cancer with the highest incidence and mortality in China.
  • the growth rat of lung cancer in China has reached as high as 465%, and the mortality rate is close to the incidence rate, accounting for about 40%of the global total.
  • Small-cell lung cancer (SCLC) is a genetically heterogeneous disease with no standardized targeted therapy options.
  • SCLC small-cell lung cancer
  • improvements in overall survival have been modest, and platinum-based chemotherapy combined with topoisomerase inhibitors remains the standard of care in SCLC.
  • patients have a limited benefit in overall survival from these treatment regimens.
  • SCLC remains a difficult-to-treat disease and is associated with a dismal prognosis in most patients. Discovering biomarkers and developing corresponding targeted treatment have been challenging.
  • FAK a non-receptor tyrosine kinase
  • the present invention is related to an improved treatment method of cancer, especially small-cell lung cancer with compound of formula I e.g. compound A.
  • the disclosure further provides combinations of compound of formula I, e.g. compound A and first-or second-line chemotherapy agents, e.g. topotecan, etoposide, or carboplatin.
  • first-or second-line chemotherapy agents e.g. topotecan, etoposide, or carboplatin.
  • the present disclosure provides a method for the treatment of cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound represented by formula I, a pharmaceutically acceptable salt or a solvate thereof;
  • R 1a and R 1b are independently hydrogen, C 1-6 alkyl, or C 3-8 cycloalkyl;
  • R 2a and R 2b are independently hydrogen, C 1-6 alkyl, or C 3-8 cycloalkyl;
  • R 3 is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or 4-8 membered heterocyclyl, wherein the heteroatom is independently N, O or S, and the number of heteroatom is 1, 2, 3 or 4;
  • R 4 is C 1-4 alkyl, or C 3-6 cycloalkyl
  • R 5 is halo
  • R 6 is C 1-4 alkyl, or C 3-6 cycloalkyl
  • R 7 is hydrogen, C 1-4 alkyl, or C 3-6 cycloalkyl
  • R 3 is C 3-6 cycloalkyl, or 4-8 membered heterocyclyl.
  • R 1a and R 1b are H.
  • R 2a and R 2b are H.
  • R 3 is 4-8 membered heterocyclyl, preferably, R 3 is
  • R 4 is C 1-4 alkyl, preferably, R 4 is isopropyl.
  • R 5 is Cl
  • R 6 is C 1-4 alkyl, preferably, R 6 is isopropyl.
  • R 7 is C 1-4 alkyl, preferably, R 7 is methyl.
  • the compound represented by formula I is a compound represented by formula I-1:
  • R 1a , R 1b , R 2a , R 2b , and R 3 are as defined in any of the embodiments.
  • the compound represented by formula I is a compound A:
  • the compound represented by formula I is 5-chloro-N 2 - (2-isopropoxy-5-methyl-4- (1- (tetrahydro-2H-pyran-4-yl) -1, 2, 3, 6-tetrahydropyridin-4-yl) phenyl) -N 4 - (2- (isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine.
  • the cancer is small-cell lung cancer.
  • the compound represented by formula I, the pharmaceutically acceptable salt thereof or the solvate thereof is administered in an amount of 10mg/day-4000 mg/day, e.g. 10 mg/day, 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 100 mg/day, 150 mg/day, 200 mg/day, 250 mg/day, 300 mg/day, 350 mg/day, 400 mg/day, 450 mg/day, 500 mg/day, 550 mg/day, 600 mg/day, 650 mg/day, 700 mg/day, 750 mg/day, 800 mg/day, 850 mg/day, 900 mg/day, 950 mg/day, 1000 mg/day, 1200 mg/day, 1500 mg/day, 2000 mg/day, 2500 mg/day, 3000 mg/day, 3500 mg/day or 4000mg/day.
  • 10mg/day-4000 mg/day e.g. 10 mg/day, 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 100 mg/
  • the compound represented by formula I, the pharmaceutically acceptable salt thereof or the solvate thereof is administered orally.
  • the compound represented by formula I, the pharmaceutically acceptable salt thereof or the solvate thereof is administered once a day, twice a day, or three times a day, e.g. once a day.
  • the compound represented by formula I, the pharmaceutically acceptable salt thereof or the solvate thereof is administered continuously until disease progression or intolerable toxicity occurs.
  • the compound represented by formula I, the pharmaceutically acceptable salt thereof or the solvate thereof is administered singly.
  • the compound represented by formula I, the pharmaceutically acceptable salt thereof or the solvate thereof is administered in combination with a chemotherapy agent.
  • the chemotherapy agent is first-or second-line chemotherapy agent, e.g. the chemotherapy agent is DNA synthesis inhibitor, DNA topoisomerase I inhibitor, or DNA topoisomerase II inhibitor, e.g. the chemotherapy agent is topotecan, etoposide, or carboplatin.
  • the chemotherapy agent is administered in an amount of 0.1mg/m 2 -1000mg/m 2 , or AUC 1mg/ml/min-100mg/ml/min, e.g. 1mg/m 2 , 2mg/m 2 , 100mg/m 2 or 5mg/ml/min.
  • the chemotherapy agent is topotecan, and is administered in an amount of 1 mg/m 2 , 1.25 mg/m 2 , 1.5 mg/m 2 or 2mg/m 2 .
  • the chemotherapy agent is etoposide, and is administered in an amount of 60–120 mg/m 2 , e.g. 60 mg/m 2 , 80 mg/m 2 , 100mg/m 2 or 120mg/m 2 .
  • the chemotherapy agent is carboplatin, and is administered in an amount of AUC 3-10 mg/ml/min, e.g. 5mg/ml/min.
  • the chemotherapy agent is topotecan, and is administered on days 1 to 5 of every 21-day cycle.
  • the chemotherapy agent is etoposide, and is administered on days 1 to 3 of every 21-day cycle.
  • the chemotherapy agent is carboplatin, and is administered on the 1st day of every 21-day cycle.
  • the chemotherapy agent is topotecan, and is administered on days 1 to 5 of every 21-day cycle, and is administered in an amount of 1.25 mg/m 2 .
  • the chemotherapy agent is etoposide, and is administered on days 1 to 3 of every 21-day cycle, and is administered in an amount of 100mg/m 2 .
  • the chemotherapy agent is carboplatin, and is administered on the 1st day of every 21-day cycle, and is administered in an amount of AUC 5mg/ml/min.
  • the chemotherapy agent is administered intravenously.
  • the chemotherapy agent is administered once a day, twice a day, or three times a day, e.g. once a day.
  • the compound represented by formula I, the pharmaceutically acceptable salt thereof or the solvate thereof, and the chemotherapy agent are administered together, simultaneously, sequentially or alternately.
  • the weight ration between the compound represented by formula I, the pharmaceutically acceptable salt thereof or the solvate thereof and the chemotherapy agent is (0.1-1000) : (0.1-1000) , e.g. 1: (30-3000) , e.g. 1: (2122-2520) or 1: (44-53) .
  • Disclosed herein is an improved treatment method for treating cancer, especially small-cell lung cancer with compound A.
  • the disclosure provides a pharmaceutical combination comprising the compound represented by formula I, the pharmaceutically acceptable salt thereof or the solvate thereof as defined in any of the embodiments, and a chemotherapy agent.
  • the chemotherapy agent is as defined in any of the embodiments.
  • the pharmaceutical combination is used for treating cancer, e.g. small-cell lung cancer.
  • the disclosure provides a pharmaceutical combination of compound A with a chemotherapy agent, e.g. topotecan, etoposide, and/or carboplatin, and further comprising a pharmaceutically acceptable carrier.
  • a chemotherapy agent e.g. topotecan, etoposide, and/or carboplatin
  • the disclosure provides a kit, comprising:
  • a second component in a second container comprising a chemotherapy agent, and optionally a pharmaceutically acceptable carrier;
  • the chemotherapy agent is as defined in any of the embodiments.
  • the present disclosure provides a use of the compound represented by formula I, the pharmaceutically acceptable salt thereof or the solvate thereof as defined in any of the embodiments in the manufacture of a medicament for the treatment of cancer.
  • the cancer is small-cell lung cancer.
  • the disclosure provides use of compound A with a chemotherapy agent, e.g. topotecan, etoposide, and/or carboplatin for treating cancer, especially small-cell lung cancer.
  • a chemotherapy agent e.g. topotecan, etoposide, and/or carboplatin for treating cancer, especially small-cell lung cancer.
  • the description "... independently” used in the present disclosure should be understood in a broad sense, meaning that each described individual is independent of each other and can be the same or different specific groups independently.
  • the description “... independently” can mean either that the specific options expressed by the same symbols in different groups do not affect each other; or that the specific options expressed by the same symbols in the same group do not affect each other.
  • halogen refers to F, Cl, Br, or I.
  • alkyl refers to linear or branched, saturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g. C 1 -C 4 ) .
  • C 1-4 alkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 4 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
  • Examples of C 1-6 alkyl include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms, e.g. n-propyl and isopropyl) , butyl (including all isomeric forms, e.g., n-butyl, isobutyl, sec-butyl, and t-butyl) .
  • cycloalkyl refers to a cyclic, saturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g. C 3 -C 8 ) , which is monocyclic or bicyclic.
  • C 3-8 cycloalkyl refers to a C 3-8 cyclic hydrocarbon radical.
  • Examples of C 3-8 cycloalkyl include, but are not limited to C 3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • heterocyclyl refers to saturated or un saturated monovalent group having a specified number of heteroatoms (e.g. 1, 2, 3, or 4) , a specified number of ring atoms (e.g. 4-8 membered) , and a specified heteroatom species (one or more independently selected from the group consisting of N, O, and S) , which is monocyclic or polycyclic. Heterocyclyl is attached to the rest of the molecule through a carbon atom or a heteroatom.
  • the term “treating” refers to therapeutic therapy.
  • the treatment refers to: (1) alleviating one or more of the biological manifestations of a disease or a condition, (2) interfering with (a) one or more points in the biological cascade that leads to a condition or (b) one or more of the biological manifestations of a condition, (3) improving one or more of the symptoms, effects or side effects associated with a condition or one or more of the symptoms, effects or side effects associated with a condition or treatment thereof, or (4) slowing the progression of one or more of the biological manifestations of a disorder or a condition.
  • the term "therapeutically effective amount” refers to an amount that is effective to elicit the desired biological or medical response, including the amount of a compound that, when administered to a subject for treating a disorder, is sufficient to effect such a treatment of the disorder.
  • the therapeutically effective amount will vary depending on the disorder, and its severity, and the age, weight, etc. of the subject to be treated.
  • the therapeutically effective amount may be in one or more doses (for example, a single dose or multiple doses may be required to achieve the desired treatment endpoint) .
  • a therapeutically effective amount may be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result is achieved.
  • Suitable doses of any co-administered compounds may optionally be lowered due to a combined effect, additive or synergistic, of the compound.
  • the term "subject" to which administration is contemplated includes any animal (e.g. humans) .
  • pharmaceutically acceptable refer to compounds, salts, compositions, dosage forms and other materials which are used in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19.
  • Pharmaceutically acceptable salts of compound 1 include those derived from suitable inorganic and organic acids and bases.
  • dose is an amount of the certain substance to be taken at one time.
  • Figure 1 shows that treatment of a range of SCLC cell lines with Compound A identifies a spectrum of responses.
  • Figure 2 shows that IC 50 for Compound A in SCLC cell lines, and SCLC cell lines harboring FAK 6, 7 are more sensitive to Compound A.
  • Figures 3-4 shows that Compound A inhibits FAK activity in a dose dependent manner.
  • Figure 5 shows that Compound A in SCLC expressing FAK slicing variants; specifically, antiproliferation effect of the combination of Compound A and topotecan in H526 cells.
  • Figure 6 shows that Compound A in SCLC expressing FAK slicing variants; specifically, synergy score of the combination of Compound A and topotecan in H526 cells.
  • Figure 7 shows that Compound A in SCLC expressing FAK slicing variants; specifically, antiproliferation effect of the combination of Compound A and topotecan in H69 cells.
  • Figure 8 shows that Compound A in SCLC expressing FAK slicing variants; specifically, synergy score of the combination of Compound A and topotecan in H69 cells.
  • Figure 9 shows that antiproliferation effect of the combination of Compound A and topotecan in H209 cells.
  • Figure 10 shows that synergy score of the combination of Compound A and topotecan in H209 cells.
  • Figure 11 shows that antiproliferation effect of the combination of Compound A and topotecan in H446 cells.
  • Figure 12 shows that synergy score of the combination of Compound A and topotecan in H446 cells.
  • Figures 13-16 shows that antiproliferation effect of the combination of Compound A and carboplatin plus etoposide in H446 cells.
  • Figures 17-24 shows that Compound A in combination with etoposide and carboplatin has synergy effect in inhibiting cell growth on H526 cell line, synergy score is calculated by SynergyFinder 3.0 Heatmaps indicating BLlSS synergy scores.
  • Figure 25 shows that Compound A enhances the antitumor effect of Topotecan; specifically, Compound A enhanced the topotecan-induced apoptosis in H446 cells.
  • Figure 28 shows that H446 cells were treated with 2 ⁇ M Compound A combined with 0.3 ⁇ M topotecan, and western blot assay was used to measure the pFAK and ⁇ H2AX expression level.
  • Figure 29 shows that H446 cells were treated with 2, 4 ⁇ M Compound A combined with 50 ⁇ M carboplatin plus 2.5 ⁇ M etoposide, and western blot assay was used to measure the pFAK and ⁇ H2AX expression level.
  • Figure 30 shows that Tumor growth of H446 xenograft mice after administration of different compounds.
  • Figure 31 shows that Response on day 22 of H446 xenograft mice after administration of different compounds.
  • Figure 32 shows that Relative tumor volume, T/C and synergy ratio of each group on day 22 after treatment, wherein ***p ⁇ 0.001, vs. Vehicle; p ⁇ 0.001, vs. APG-2449 100mg/kg; p ⁇ 0.01, vs. Topotecan 1 mg/kg; ⁇ p ⁇ 0.001, vs. Carboplatin 30 mg/kg + Etoposide 15 mg/kg.
  • Example 1 SCLC cell lines harboring FAK 6, 7 are more sensitive to Compound A compared to cell line expressing FAK WT
  • DMS-114, H446, H209, H146, H889, H69 and H526 cell lines are purchased from Cobioer company or SIBCB.
  • H446, H209, H146, H889 and H526 cells are cultured in RPMI 1640 (gibco, Cat. C11875500BT) with 10%FBS (SIGMA, Cat. F8318) , 1%penicillin /streptomycin (gibco, Cat. 15140-122) .
  • DMS-114 is cultured in Waymouth’s medium (gibco, Cat. 11220035) with 10%FBS (SIGMA, Cat. F8318) , 1%penicillin /streptomycin (gibco, Cat. 15140-122) .
  • Cell viability was assessed using the Luminescent Cell Viability Assay.
  • the in vitro proliferation inhibitory effect of Compound A was evaluated on the DMS-114, H446, H209, H146, H889, H69 and H526 cell lines. All cells were treated with Compound A at indicated concentrations for 72 hours.
  • CCG Cell titer-Glo
  • Example 2 Compound A inhibits FAK activity in a dose dependent manner
  • H446, H209, H69 and H526 cell lines as described in example 1 were used for drug combination study.
  • CTG assay was used to assess cell viability.
  • Compound A is from Ascentage as described in example 1.
  • Topotecan (S9321) carboplatin (S1215) and etoposide (S1225) are purchased from Selleckchem.
  • H526, H69, H446 and H 209 cells were treated with topotecan alone or in combination with Compound A for 72 hours.
  • H446 and H526 cells were treated with etoposide plus carboplatin alone or in combination with Compound A for 72 hours.
  • Example 4 Compound A combined with topotecan or etoposide plus carboplatin enhanced DNA damage and apoptosis in SCLC cell lines
  • H446 and H69 cell lines as described in example 1 were used for apoptosis assay and western blot assay.
  • H446 cells were treated with Compound A or topotecan alone or in combination for 48 hours. Then annexin v/PI staining was performed to assess the cell apoptosis by flow cytometry.
  • western blot assay H446 or H69 cells were treated with Compound A or chemotherapeutic agents alone or in combination for 48 hours.
  • Total cell apoptosis rate of H446 is shown in Figures 25-27.
  • inhibition of FAK by Compound A can enhance the DAN damage react induced by chemotherapeutic agents. The results are illustrated in Figures 28-29.
  • Compound A can increase the expression of ⁇ H2AX, cleaved caspase 3 or cleaved PARP when combined with topotecan or carboplatin plus etoposide, indicating that inhibition of FAK activity by Compound A enhance the DNA damage react and cell apoptosis induced by chemotherapeutic agents.
  • Example 5 Compound A synergistically enhanced the antitumor effects of chemotherapeutic agents in the H446 xenograft model.
  • mice Female Balb/c nude mice aged 6 to 8 weeks were obtained from Gempharmatech. Mice were maintained in laminar flow units in sterile filter-top cages with Alpha-Dri bedding in a 12/12 dark/light cycle, at controlled temperature (20–26°C) and humidity conditions (30–70%) . 5x10 6 /mouse H446 cells in 0.2 mL 30%Matrigel in PBS were implanted subcutaneously into the flank of mice. 5x10 6 /mouse. Mice were randomized into groups once the tumors had attained a volume of 120 mm 3 .
  • Tumor-bearing mice were treated with Compound A (PO, QD ⁇ 21D) , topotecan (PO, QD*5 x 3W) , etoposide + carboplatin (IP, QW ⁇ 3W) , Compound A + topotecan, Compound A + etoposide + carboplatin or vehicle.
  • Results are shown in Figures 30-32.
  • Compound A 100 mg/kg demonstrated antitumor effect, with T/C (%) values of 92.1.
  • Treatment with topotecan, and carboplatin plus etoposide resulted in a T/C (%) of 11.69 and 21.03 respectively.
  • T/C of Compound A+topotecan is 0.49%
  • T/C of Compound A+carboplatin+etoposide is 5.09 were better than single agent treating group.
  • Compound A synergistically enhanced the antitumor effects of topotecan (synergy ratio: 22.08) and etoposide plus carboplatin (synergy ratio: 3.81) in the H446 xenograft model.
  • Compound A synergistically enhanced antitumor effects of both first-and second-line chemotherapy commonly used in SCLC.
  • Compound A might sensitize SCLC cells to chemotherapy by increasing DNA damage and apoptosis.
  • Compound A sensitized FAK 6, 7 -expressing SCLC cells to chemotherapy, such as topotecan or etoposide and carboplatin, in a synergistic manner. This effect was not observed in FAK WT cells. Mechanistically, Compound A combined with topotecan led to elevated DNA damage and increased apoptosis compared with either Compound A or topotecan alone.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une méthode de traitement du cancer, en particulier du cancer du poumon à petites cellules avec un composé de formule I, par exemple le composé A, le sel pharmaceutiquement acceptable ou le solvate de celui-ci, en tant qu'inhibiteur de kinase d'adhésion focale. L'invention concerne une combinaison pharmaceutique ou un kit comprenant le composé et un agent de chimiothérapie, par exemple le topotécan, l'étoposide ou le carboplatine.
PCT/CN2025/092841 2024-05-06 2025-05-06 Méthode de traitement avec un inhibiteur de kinase d'adhérence focale Pending WO2025232723A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2024091286 2024-05-06
CNPCT/CN2024/091286 2024-05-06

Publications (1)

Publication Number Publication Date
WO2025232723A1 true WO2025232723A1 (fr) 2025-11-13

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PCT/CN2025/092841 Pending WO2025232723A1 (fr) 2024-05-06 2025-05-06 Méthode de traitement avec un inhibiteur de kinase d'adhérence focale

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WO (1) WO2025232723A1 (fr)

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