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WO2021089005A1 - Utilisation d'un inhibiteur de fgfr - Google Patents

Utilisation d'un inhibiteur de fgfr Download PDF

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Publication number
WO2021089005A1
WO2021089005A1 PCT/CN2020/127211 CN2020127211W WO2021089005A1 WO 2021089005 A1 WO2021089005 A1 WO 2021089005A1 CN 2020127211 W CN2020127211 W CN 2020127211W WO 2021089005 A1 WO2021089005 A1 WO 2021089005A1
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WIPO (PCT)
Prior art keywords
compound
fgfr
cholangiocarcinoma
cancer
pharmaceutically acceptable
Prior art date
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PCT/CN2020/127211
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English (en)
Chinese (zh)
Inventor
王彩霞
王玲玲
张阳
李桂霞
祁欢欢
赵晶
李筱
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CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
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CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
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Priority to CN202080076195.1A priority Critical patent/CN114641293B/zh
Publication of WO2021089005A1 publication Critical patent/WO2021089005A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention belongs to the field of medicine. More specifically, the present invention relates to an FGFR inhibitor or a pharmaceutically acceptable salt thereof for the treatment of FGFR-related tumors, a pharmaceutical composition containing the same, a method for treating FGFR-related tumors using a drug containing the same, and the preparation thereof Use in drugs for treating FGFR-related tumors.
  • Fibroblast growth factor receptor is a receptor for fibroblast growth factor (FGF) signal transduction, and its family consists of four members (FGFR1-4). Through FGFR, FGF plays an important role in many physiological regulation processes such as cell proliferation, cell differentiation, cell migration and angiogenesis.
  • FGF signaling pathway high expression, gene amplification, gene mutation, chromosome recombination, etc.
  • pathological processes such as tumor cell proliferation, migration, invasion and angiogenesis
  • FGFR is in many tumors
  • FGFR2 fusion mutations occur in about 10-20% of patients with intrahepatic cholangiocarcinoma; FGFR3 gene changes in bladder cancer have a strong correlation with low-grade pathological and clinical low-stage cancers, more than 70%
  • the pathological low-grade non-invasive urothelial papilloma contains FGFR3 mutation; and high expression of FGFR1, FGFR2 and FGFR3 are found in gastric cancer tissues and gastric cancer cells. Therefore, FGFR has become an important therapeutic target, attracting a wide range of research and development interest.
  • inhibitors that target the kinase domain of the FGFR membrane can be divided into ATP-competitive inhibitors, non-ATP-competitive reversible inhibitors, and irreversible inhibitors.
  • non-ATP-competitive reversible inhibitors and irreversible inhibitors affect kinases.
  • the inhibitory activity is not affected by the high ATP concentration in the cell and in the body.
  • some FGFR-targeted drugs for the treatment of the above-mentioned tumor diseases have entered the clinical trial stage.
  • Balversa Erdafitinib
  • FGFR reversible inhibitor targeted drugs have become the world's first pandemic drug for metastatic urothelial cancer approved by the FDA.
  • FGFR1-4 inhibitors for example, BGJ-398, Debio-1347 and TAS-120, etc.
  • solid tumors such as urothelial cell carcinoma and liver cancer.
  • the structural formulas of the above drugs are as follows:
  • pan-FGFR pan-FGFR
  • irreversible inhibitors such as TAS-120 Patients who are resistant to BGJ-398 are still effective, showing the unique advantages of irreversible inhibitors. But so far, no FGFR1-4 irreversible inhibitor has been approved for marketing at home and abroad.
  • liver cancer Primary liver cancer
  • liver cancer is a relatively common malignant tumor and the fourth leading cause of cancer deaths in the world, posing a serious threat to human life and health.
  • Liver cancer mainly includes hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and combined hepatocellular cholangiocarcinoma (c-CC-CC).
  • HCC hepatocellular carcinoma
  • ICC intrahepatic cholangiocarcinoma
  • c-CC-CC combined hepatocellular cholangiocarcinoma
  • Liver cancer has no obvious clinical symptoms in the early stage, and is often found in the middle and late stages, with high malignancy, high recurrence rate, poor treatment effect, and poor prognosis.
  • the clinical treatment of liver cancer mainly includes surgical treatment, transcatheter arterial chemoembolization (TACE), radiotherapy and chemotherapy.
  • TACE transcatheter arterial chemoembolization
  • Sorafenib is currently the only molecularly targeted drug approved for the treatment of advanced liver cancer, but its effect on liver cancer patients with liver function Child-Pugh grade B is still poor.
  • Urothelial cancer is a common malignant tumor worldwide, and it is also one of the most common clinical malignancies in urology in my country. Among them, 90%-95% of urothelial cancers are bladder cancer. Urothelial cell carcinoma is mostly non-muscular invasive at the first diagnosis, but it has a high recurrence rate; and with the increase in the number of recurrences, the malignancy of the tumor will increase and turn into a muscular invasive tumor. Patients with metastatic urothelial cancer with FGFR gene alterations have a poor prognosis and a low response rate to treatment. There are significant clinical needs that are far from being met in this type of patients.
  • Gastric cancer is also one of the most common malignant tumors in the world, with a relatively poor prognosis and a serious threat to human health. Due to the lack of a mature early screening system and the atypical symptoms of early gastric cancer and the low detection rate, most patients are already in the advanced stage when they are diagnosed.
  • Today's treatment measures for gastric cancer mainly include surgical treatment, systemic application of chemical drugs, radiotherapy and molecular targeted drug therapy. Targeted therapy is a drug treatment aimed at specific tumor targets.
  • clinical studies on targeted therapy of gastric cancer have few successes and many failures.
  • Cholangiocarcinoma is a malignant tumor of epithelial cells with different characteristics of cholangiocarcinoma. The incidence has increased by nearly 20% in the past 10 years, accounting for about 3% of gastrointestinal tumors and 10-15% of hepatobiliary malignancies. According to anatomical location, cholangiocarcinoma can be divided into intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma (eCCA), the latter is further divided into hilar cholangiocarcinoma (pCCA) and distal cholangiocarcinoma (distal cholangiocarcinoma) , DCCA).
  • pCCA hilar cholangiocarcinoma
  • DCCA distal cholangiocarcinoma
  • FGFR inhibitors have shown promise in clinical trials of cholangiocarcinoma.
  • the FGFR inhibitor BGJ-398 has obtained excellent phase II trial results in advanced cholangiocarcinoma with FGFR gene fusion, mutation, and amplification, and objective remission
  • the rate and disease control rate in FGFR gene fusion patients reached 18.8% and 83.3%.
  • Intrahepatic cholangiocarcinoma refers to malignant tumors of bile duct epithelium located in the liver at level 2 and above. It is also called intrahepatic cholangiocarcinoma. It belongs to a type of primary liver cancer (accounting for 10% to 15%). Can be attributed to a type of cholangiocarcinoma (about 10%). Intrahepatic cholangiocarcinoma is highly malignant, has strong invasion and lymph node metastasis characteristics, and is difficult to diagnose early. The prognosis of the patient is poor. The overall 5-year survival rate is less than 10%, and the median survival time after surgical resection is 36 months.
  • Intrahepatic cholangiocarcinoma is insensitive to traditional chemotherapy, radiotherapy and recent tumor immunotherapy. There is no standard treatment for cholangiocarcinoma patients who have failed chemotherapy with the first-line gemcitabine.
  • FGFR inhibitors are in different stages of clinical research on cholangiocarcinoma, such as BGJ-398 (reversible selective inhibitor), ARQ087 (ATP competitive inhibitor), TAS-120 (irreversible pan-FGFR inhibitor) Et al.
  • the first FGFR inhibitor reported in cholangiocarcinoma was BGJ-398.
  • Further studies found polyclonal secondary mutations in the kinase domain of FGFR2, including 3 cases The FGFR2V564F gene mutation exists in all patients.
  • TAS-120 is a highly selective and irreversible pan-FGFR inhibitor. Studies have shown that TAS-120 has clinical effects on BGJ-398-resistant intrahepatic cholangiocarcinoma patients, and can inhibit a variety of secondary FGFR2 mutations. However, there is no literature that discloses the cell-level inhibitory activity data of TAS-120. Currently, no targeted drugs for the treatment of intrahepatic cholangiocarcinoma have been approved for marketing.
  • WO2019034076A1 discloses FGFR inhibitors and their medical uses, including compound A (Example 2).
  • This patent application discloses the evaluation results of compound A on FGFR wild-type kinase in vitro inhibitory activity, the evaluation results on mutant kinase in vitro inhibitory activity and the pharmacokinetic evaluation results in mice, but it does not disclose which diseases Compound A can be used for. the treatment.
  • An object of the present invention is to provide a use of Fibroblast Growth Factor Receptor (FGFR) inhibitor compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of FGFR-related tumors.
  • FGFR Fibroblast Growth Factor Receptor
  • Another object of the present invention is to provide an FGFR inhibitor compound A or a pharmaceutically acceptable salt thereof, which is used for the treatment of FGFR-related tumors.
  • Another object of the present invention is to provide a method for treating FGFR-related tumors, the method comprising administering to a subject or patient a drug containing a therapeutically effective amount of an FGFR inhibitor compound A or a pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to provide a pharmaceutical composition for the treatment of FGFR-related tumors, which comprises an FGFR inhibitor compound A or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier.
  • a technical problem to be solved by the present invention is to provide a small molecule compound with excellent FGFR1-4 wild-type and mutant kinase inhibitory activity, and a pharmaceutical composition, use and treatment method thereof.
  • Another technical problem to be solved by the present invention is to provide a small molecule with excellent FGFR1-4 wild-type and mutant kinase inhibitory activity and excellent in vitro/in vivo anti-FGFR-related tumors (especially digestive or urinary system tumors) activity Compound and its pharmaceutical composition, use and treatment method.
  • Another technical problem to be solved by the present invention is to provide an excellent FGFR1-4 wild-type and mutant kinase inhibitory activity and excellent in vitro/in vivo anti-FGFR-related tumor (especially digestive or urinary system tumors) activity, and has Small molecule compounds with good safety and their pharmaceutical compositions, uses and treatment methods.
  • Another technical problem to be solved by the present invention is to provide an excellent FGFR1-4 wild-type and mutant kinase inhibitory activity and excellent in vitro/in vivo anti-FGFR-related tumor (especially digestive or urinary system tumors) activity, and has Small molecule compounds with excellent plasma stability and safety, and pharmaceutical compositions, uses and treatment methods thereof.
  • an FGFR inhibitor compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of FGFR-related tumors, wherein the compound A has The structure is as follows:
  • the FGFR-related tumor is one or more of digestive or urinary system tumors.
  • the FGFR-related tumor is any one of gastric cancer, liver cancer, urothelial cancer, cholangiocarcinoma, or any combination thereof.
  • the FGFR-related tumor is gastric cancer.
  • the gastric cancer is gastric cancer with FGFR2 gene amplification.
  • the FGFR-related tumor is liver cancer.
  • the liver cancer is a liver cancer with high FGFR4/FGF19 expression.
  • the liver cancer is a liver cancer with high FGFR3 expression.
  • the liver cancer is any one of hepatocellular carcinoma, intrahepatic cholangiocarcinoma, mixed liver cancer, or any combination thereof.
  • the FGFR-related tumor is urothelial carcinoma.
  • the urothelial cancer is bladder cancer.
  • the bladder cancer is a bladder cancer with high FGFR3 expression and FGFR3-TACC3 fusion.
  • the FGFR-related tumor is cholangiocarcinoma.
  • the cholangiocarcinoma is a cholangiocarcinoma with high FGFR2 expression.
  • the cholangiocarcinoma is any one of intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma, distal cholangiocarcinoma, or any combination thereof.
  • the cholangiocarcinoma is intrahepatic cholangiocarcinoma.
  • the compound A or a pharmaceutically acceptable salt thereof is the only active ingredient in the drug.
  • the compound A or a pharmaceutically acceptable salt thereof is used in combination with one or more other targeted drugs or chemotherapeutics.
  • the drug is formulated into a clinically accepted formulation.
  • the preparation is an oral preparation, an injection preparation or a topical preparation.
  • the compound A or a pharmaceutically acceptable salt thereof is administered in a daily dosage range from about 0.001 mg/kg to about 1000 mg/kg. In a preferred embodiment, the compound A or a pharmaceutically acceptable salt thereof is administered in a daily dosage range from about 0.01 mg/kg to about 100 mg/kg. In a preferred embodiment, the compound A or a pharmaceutically acceptable salt thereof is administered in a daily dosage range from about 0.02 mg/kg to about 50 mg/kg. In a preferred embodiment, the compound A or a pharmaceutically acceptable salt thereof is administered in a daily dosage range from about 0.03 mg/kg to about 20 mg/kg.
  • the medicament contains a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.
  • the therapeutically effective amount is 0.001-1000 mg.
  • the therapeutically effective amount is 0.01-100 mg.
  • the therapeutically effective amount is 0.1-50 mg.
  • the therapeutically effective amount is 0.5-30 mg.
  • the compound A or a pharmaceutically acceptable salt thereof is administered in a single dose or in divided doses.
  • the drug is administered orally, by injection, topical, or in vitro. In a preferred embodiment, the drug is administered orally or by injection.
  • an FGFR inhibitor compound A or a pharmaceutically acceptable salt thereof for the treatment of FGFR-related tumors wherein the compound A has the following structure:
  • the FGFR-related tumor is one or more of digestive or urinary system tumors.
  • the FGFR-related tumor is any one of gastric cancer, liver cancer, urothelial cancer, cholangiocarcinoma, or any combination thereof.
  • the FGFR-related tumor is gastric cancer.
  • the gastric cancer is gastric cancer with FGFR2 gene amplification.
  • the FGFR-related tumor is liver cancer.
  • the liver cancer is a liver cancer with high FGFR4/FGF19 expression.
  • the liver cancer is a liver cancer with high FGFR3 expression.
  • the liver cancer is any one of hepatocellular carcinoma, intrahepatic cholangiocarcinoma, mixed liver cancer, or any combination thereof.
  • the FGFR-related tumor is urothelial carcinoma.
  • the urothelial cancer is bladder cancer.
  • the bladder cancer is a bladder cancer with high FGFR3 expression and FGFR3-TACC3 fusion.
  • the FGFR-related tumor is cholangiocarcinoma.
  • the cholangiocarcinoma is a cholangiocarcinoma with high FGFR2 expression.
  • the cholangiocarcinoma is any one of intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma, distal cholangiocarcinoma, or any combination thereof.
  • the cholangiocarcinoma is intrahepatic cholangiocarcinoma.
  • the compound A or a pharmaceutically acceptable salt thereof is used as the sole active ingredient.
  • the compound A or a pharmaceutically acceptable salt thereof is used in combination with one or more other targeted drugs or chemotherapeutic drugs.
  • the compound A or a pharmaceutically acceptable salt thereof is formulated into a clinically acceptable preparation.
  • the preparation is an oral preparation, an injection preparation or a topical preparation.
  • the compound A or a pharmaceutically acceptable salt thereof is administered in a daily dosage range from about 0.001 mg/kg to about 1000 mg/kg. In a preferred embodiment, the compound A or a pharmaceutically acceptable salt thereof is administered in a daily dosage range from about 0.01 mg/kg to about 100 mg/kg. In a preferred embodiment, the compound A or a pharmaceutically acceptable salt thereof is administered in a daily dosage range from about 0.02 mg/kg to about 50 mg/kg. In a preferred embodiment, the compound A or a pharmaceutically acceptable salt thereof is administered in a daily dosage range from about 0.03 mg/kg to about 20 mg/kg.
  • the compound A or a pharmaceutically acceptable salt thereof is formulated in a medicament in a therapeutically effective amount.
  • the therapeutically effective amount is 0.001-1000 mg.
  • the therapeutically effective amount is 0.01-100 mg.
  • the therapeutically effective amount is 0.1-50 mg.
  • the therapeutically effective amount is 0.5-30 mg.
  • the compound A or a pharmaceutically acceptable salt thereof is administered in a single dose or in divided doses.
  • the compound A or a pharmaceutically acceptable salt thereof is administered orally, by injection, topical, or in vitro. In a preferred embodiment, the compound A or a pharmaceutically acceptable salt thereof is administered by oral administration or injection.
  • FGFR inhibitor compound A or a pharmaceutically acceptable salt thereof Drug, wherein the compound A has the following structure:
  • the FGFR-related tumor is one or more of digestive or urinary system tumors.
  • the FGFR-related tumor is any one of gastric cancer, liver cancer, urothelial cancer, cholangiocarcinoma, or any combination thereof.
  • the FGFR-related tumor is gastric cancer.
  • the gastric cancer is gastric cancer with FGFR2 gene amplification.
  • the FGFR-related tumor is liver cancer.
  • the liver cancer is a liver cancer with high FGFR4/FGF19 expression.
  • the liver cancer is a liver cancer with high FGFR3 expression.
  • the liver cancer is any one of hepatocellular carcinoma, intrahepatic cholangiocarcinoma, mixed liver cancer, or any combination thereof.
  • the FGFR-related tumor is urothelial carcinoma.
  • the urothelial cancer is bladder cancer.
  • the bladder cancer is a bladder cancer with high FGFR3 expression and FGFR3-TACC3 fusion.
  • the FGFR-related tumor is cholangiocarcinoma.
  • the cholangiocarcinoma is a cholangiocarcinoma with high FGFR2 expression.
  • the cholangiocarcinoma is any one of intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma, distal cholangiocarcinoma, or any combination thereof.
  • the cholangiocarcinoma is intrahepatic cholangiocarcinoma.
  • the compound A or a pharmaceutically acceptable salt thereof is administered as the sole active ingredient.
  • the compound A or a pharmaceutically acceptable salt thereof is administered in combination with one or more other targeted drugs or chemotherapeutic drugs.
  • the drug is formulated into a clinically accepted formulation.
  • the preparation is an oral preparation, an injection preparation or a topical preparation.
  • the compound A or a pharmaceutically acceptable salt thereof is administered in a daily dosage range from about 0.001 mg/kg to about 1000 mg/kg. In a preferred embodiment, the compound A or a pharmaceutically acceptable salt thereof is administered in a daily dosage range from about 0.01 mg/kg to about 100 mg/kg. In a preferred embodiment, the compound A or a pharmaceutically acceptable salt thereof is administered in a daily dosage range from about 0.02 mg/kg to about 50 mg/kg. In a preferred embodiment, the compound A or a pharmaceutically acceptable salt thereof is administered in a daily dosage range from about 0.03 mg/kg to about 20 mg/kg.
  • the therapeutically effective amount is 0.001-1000 mg. In a preferred embodiment, the therapeutically effective amount is 0.01-100 mg. In a preferred embodiment, the therapeutically effective amount is 0.1-50 mg. In a preferred embodiment, the therapeutically effective amount is 0.5-30 mg.
  • the compound A or a pharmaceutically acceptable salt thereof is administered in a single dose or in divided doses.
  • the compound A or a pharmaceutically acceptable salt thereof is administered orally, by injection, topical, or in vitro. In a preferred embodiment, the compound A or a pharmaceutically acceptable salt thereof is administered by oral administration or injection.
  • a pharmaceutical composition for the treatment of FGFR-related tumors which comprises an FGFR inhibitor compound A or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable , wherein the compound A has the following structure:
  • the FGFR-related tumor is one or more of digestive or urinary system tumors.
  • the FGFR-related tumor is any one of gastric cancer, liver cancer, urothelial cancer, cholangiocarcinoma, or any combination thereof.
  • the FGFR-related tumor is gastric cancer.
  • the gastric cancer is gastric cancer with FGFR2 gene amplification.
  • the FGFR-related tumor is liver cancer.
  • the liver cancer is a liver cancer with high FGFR4/FGF19 expression.
  • the liver cancer is a liver cancer with high FGFR3 expression.
  • the liver cancer is any one of hepatocellular carcinoma, intrahepatic cholangiocarcinoma, mixed liver cancer, or any combination thereof.
  • the FGFR-related tumor is urothelial carcinoma.
  • the urothelial cancer is bladder cancer.
  • the bladder cancer is a bladder cancer with high FGFR3 expression and FGFR3-TACC3 fusion.
  • the FGFR-related tumor is cholangiocarcinoma.
  • the cholangiocarcinoma is a cholangiocarcinoma with high FGFR2 expression.
  • the cholangiocarcinoma is any one of intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma, distal cholangiocarcinoma, or any combination thereof.
  • the cholangiocarcinoma is intrahepatic cholangiocarcinoma.
  • the compound A or a pharmaceutically acceptable salt thereof is the only active ingredient in the pharmaceutical composition.
  • the pharmaceutical composition also contains one or more other targeted drugs or chemotherapeutic drugs as active ingredients.
  • the pharmaceutical composition is formulated into a clinically accepted formulation.
  • the preparation is an oral preparation, an injection preparation or a topical preparation.
  • the compound A or a pharmaceutically acceptable salt thereof is administered in a daily dosage range from about 0.001 mg/kg to about 1000 mg/kg. In a preferred embodiment, the compound A or a pharmaceutically acceptable salt thereof is administered in a daily dosage range from about 0.01 mg/kg to about 100 mg/kg. In a preferred embodiment, the compound A or a pharmaceutically acceptable salt thereof is administered in a daily dosage range from about 0.02 mg/kg to about 50 mg/kg. In a preferred embodiment, the compound A or a pharmaceutically acceptable salt thereof is administered in a daily dosage range from about 0.03 mg/kg to about 20 mg/kg.
  • the pharmaceutical composition contains a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.
  • the therapeutically effective amount is 0.001-1000 mg.
  • the therapeutically effective amount is 0.01-100 mg.
  • the therapeutically effective amount is 0.1-50 mg.
  • the therapeutically effective amount is 0.5-30 mg.
  • the compound A or a pharmaceutically acceptable salt thereof is administered in a single dose or in divided doses.
  • the pharmaceutical composition is administered by oral administration, injection administration, topical administration or in vitro administration. In a preferred embodiment, the pharmaceutical composition is administered by oral administration or injection.
  • the present invention evaluated the in vitro kinase inhibitory activity of compound A against FGFR1-4 wild-type and mutant types and compared with The proliferation inhibitory activity of FGFR-related exemplary digestive or urinary system tumors (including gastric cancer, liver cancer, bladder cancer, and cholangiocarcinoma) models, and the inhibitory effect of compound A on tumor growth was further evaluated for several tumor xenograft models.
  • FGFR-related exemplary digestive or urinary system tumors including gastric cancer, liver cancer, bladder cancer, and cholangiocarcinoma
  • the present invention measured the plasma stability of compound A in the human and mouse plasma stability test, and the structure was similar to the reference compound (Example 8 in WO2019034076A1 (S configuration)) A comparison was made.
  • the results of plasma stability show that compound A has better stability in both mouse and human plasma.
  • irreversible inhibitors enhance their affinity with the target through covalent bonding with the target protein, which is the fundamental reason why irreversible inhibitors exhibit high biological activity.
  • affinity-enhancing effect of irreversible inhibitors will also occur on off-target sites, resulting in enhanced toxic and side effects [see Yang Bo et al. Research Progress on Small Molecule Covalent Inhibitors, Acta Pharmaceutical Sciences, 2014 , 49(2):158-165].
  • the present invention detects the off-target effects of compound A on a variety of important non-target kinases, and the results show that compound A has low off-target effects.
  • the present invention conducted safety pharmacology tests and acute toxicity tests on dogs and mice. The results show that compound A has no significant effect on the detection indicators, and the safety is good.
  • compound A has the activity of selectively inhibiting FGFR1-4, has good inhibitory activity on both wild-type and mutant FGFR1-4, and can significantly inhibit the abnormality of FGFR1-4.
  • Compound A refers to a compound with the following structure as an FGFR inhibitor:
  • “Pharmaceutically acceptable salt” refers to a conventional non-toxic salt formed by the reaction of Compound A of the present invention with an inorganic acid, organic acid, inorganic base or organic base.
  • the salt is within the scope of reliable medical judgment and is suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, and reasonable benefits/risks Commensurate.
  • a pharmaceutically acceptable base addition salt or acid addition salt can be obtained by contacting compound A with a sufficient amount of non-toxic acid or base in a pure solution or a suitable inert solvent.
  • “Pharmaceutically acceptable carrier” refers to a carrier suitable for formulating a pharmaceutical composition of Compound A or a pharmaceutically acceptable salt thereof or a clinically accepted preparation thereof.
  • the carrier is within the scope of reliable medical judgment and is suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, and reasonable benefits/risks Commensurate.
  • FGFR refers to fibroblast growth factor receptor, which is a receptor for fibroblast growth factor signaling, and its family consists of four members (FGFR1-4). Through FGFR, FGF plays an important role in many physiological regulation processes such as cell proliferation, cell differentiation, cell migration and angiogenesis.
  • FGFR-related tumors refer to tumors whose occurrence or development is closely related to the expression and activation of any one or any combination of FGFR1-4, including but not limited to gastric cancer, bladder cancer, urothelial cancer, liver cancer, Cholangiocarcinoma (eg intrahepatic cholangiocarcinoma).
  • Targeteted drug refers to a targeted drug that is clinically used to treat tumor-related diseases. It is endowed with a targeting ability to enable the active ingredient or its carrier to target a specific target lesion site, and accumulate or release the active ingredient at that site , To form a relatively high concentration, thereby improving the curative effect while inhibiting side effects and reducing damage to normal tissues and cells.
  • “Chemotherapeutic drugs” refer to drugs that can act on different links in the growth and reproduction of tumor cells, inhibit or kill tumor cells, and are clinically used to treat tumor-related diseases. It is currently one of the main methods of treating tumors.
  • Clinically accepted preparations are within the scope of reliable medical judgment, suitable for use in contact with human and animal tissues, without excessive toxicity, irritation, allergic reactions or other problems or complications, and A formulation with a reasonable benefit/risk ratio commensurate.
  • the clinically accepted preparations include oral preparations, injection preparations, and topical preparations.
  • the dosage and frequency of administration of the compound A or its pharmaceutically acceptable salt can be performed by conventional methods such as modeling, dose escalation studies, or clinical trials, and by considering the characteristics and severity of the disease to be treated. The degree, age, general condition and weight of the patient, as well as the specific compound administered, its pharmacokinetic properties, and the route of administration are determined.
  • a suitable daily dosage range of the compound A or a pharmaceutically acceptable salt thereof is from about 0.001 mg/kg to about 1000 mg/kg; preferably, from about 0.01 mg/kg to about 100 mg/kg; further Preferably, from about 0.02mg/kg to about 50mg/kg; still more preferably, from about 0.03mg/kg to about 20mg/kg (wherein, "kg” refers to the administration object (ie, the subject Or the weight of the patient).
  • the daily dose of compound A or its pharmaceutically acceptable salt is 0.001 mg-1000 mg, and more preferably, the daily dose of compound A or its pharmaceutically acceptable salt is 0.01-1000 mg.
  • the daily dose of Compound A or its pharmaceutically acceptable salt is 0.1-50 mg; More preferably, the daily dose of Compound A or its pharmaceutically acceptable salt is 0.5-30mg; More preferably, the daily dosage of Compound A or its pharmaceutically acceptable salt is 0.1mg, 0.5mg, 1mg, 2mg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 36mg, 40mg, 45mg, 50mg, 55mg, 60mg, 70mg, 72mg, 100mg, 200mg, 500mg, 800mg, 1000mg, given in single or divided doses.
  • the compound A or a pharmaceutically acceptable salt thereof is included in the drug or pharmaceutical composition in a therapeutically effective amount.
  • the therapeutically effective amount is preferably 0.001-1000 mg, more preferably 0.01-100 mg, still more preferably 0.1-50 mg, still more preferably 0.5-30 mg, administered in a single dose or in divided doses.
  • the therapeutically effective amount, administration dose or administration dose of the compound A or a pharmaceutically acceptable salt thereof is calculated as compound A.
  • subjects or patients suffering from FGFR-related tumors can be human and non-human mammals such as mice, rats, guinea pigs, cats, dogs, cows, horses, sheep, pigs, monkeys, etc., more preferably humans. .
  • FGFR fibroblast growth factor receptor
  • liver cancer is hepatocellular carcinoma, intrahepatic cholangiocarcinoma, and mixed liver cancer.
  • the drug contains a therapeutically effective amount of the inhibitor, the therapeutically effective amount is preferably 0.001-1000 mg; it can be administered in a single dose or in divided doses.
  • the present invention also relates to the following embodiments:
  • cholangiocarcinoma includes intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma and distal cholangiocarcinoma; preferably intrahepatic cholangiocarcinoma.
  • the medicine contains a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof, and the therapeutically effective dose is preferably 0.001 mg-1000 mg, more preferably 0.01-100 mg, more preferably 0.1-50 mg, still more preferably 0.5-30 mg; it can be administered in a single dose or in divided doses.
  • a method for treating FGFR-related tumor diseases characterized in that a drug containing a therapeutically effective dose of Compound A or a pharmaceutically acceptable salt thereof is administered to a subject or patient.
  • the cholangiocarcinoma includes intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma, and distal cholangiocarcinoma; preferably, it is intrahepatic cholangiocarcinoma.
  • the administration may be oral administration, injection administration, topical administration or in vitro administration, preferably oral administration or injection administration.
  • Example 1 Evaluation of FGFR1-4 wild-type kinase inhibitory activity in vitro
  • the 33 P-ATP membrane filtration experiment was used to determine the inhibitory effect of test compound A on each wild-type FGFR kinase.
  • Buffer conditions 20mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (Hepes) (pH 7.5), 10mM MgCl 2 , 1mM EGTA, 0.02% (v/v%) benzze 35 (Brij35) ), 0.02 mg/mL BSA, 0.1 mM Na 3 VO 4 , 2 mM DTT, 1% (v/v%) DMSO.
  • Test procedure At room temperature, the test compound was dissolved in DMSO to prepare a 10 mM solution for later use. Add the substrate (see Table 1) to the newly prepared reaction buffer, add the specific kinase (see Table 2) to the substrate solution, and mix gently. The sonic technology (Echo550) was used to transfer the compound dissolved in DMSO to the kinase reaction mixture. The initial concentration of the test compound in the reaction mixture was 10 ⁇ M, and a total of 10 concentrations were diluted by 4 times. After 15 minutes of incubation, 33 P-ATP (illuminance 0.01 ⁇ Ci/ ⁇ L final) was added to the reaction system to start the reaction.
  • kinase activity data is expressed as the ratio of the kinase activity of the test well (containing the test compound) and the blank well (only containing DMSO).
  • the IC 50 value is obtained by curve fitting with Prism4 software (GraphPad). The experimental results are shown in Table 3.
  • Table 3 Activity of test compounds against FGFR1-4 wild-type kinase (IC 50 , nM)
  • TAS-120 was purchased from Glpbio, catalog number GC191561.
  • the compound A of the present invention can significantly inhibit the activity of FGFR1-4 wild-type kinase, and the effect is better than that of the reference compound TAS-120.
  • Test method Thaw the frozen plasma for 10-20 minutes. After the plasma is completely thawed, place it in a centrifuge and centrifuge at 3220 ⁇ g (centrifugal force) for 5 minutes to remove suspended solids and sediments. Measure the plasma pH value, and adjust the pH to the range of 7.40 ⁇ 0.10 with 1% (v/v%) phosphoric acid solution or 1M sodium hydroxide solution. Prepare 96-well incubation plates, named T0 (0min), T10 (10min), T30 (30min), T60 (60min), T120 (120min).
  • the 33 P-ATP membrane filtration experiment was used to determine the inhibitory effect of test compound A on each mutant FGFR kinase.
  • Buffer conditions 20 mM Hepes (pH 7.5), 10 mM MgCl 2 , 1 mM EGTA, 0.02% Brij35, 0.02 mg/mL BSA, 0.1 mM Na 3 VO 4 , 2 mM DTT, 1% DMSO.
  • Test procedure Add the substrate (see Table 5) to the newly prepared reaction buffer, add the specific kinase (see Table 6) to the substrate solution, and mix gently.
  • the sonic technology (Echo550) was used to transfer the compound dissolved in DMSO to the kinase reaction mixture.
  • the initial concentration of the test compound in the reaction mixture was 10 ⁇ M, and a total of 10 concentrations were diluted by 4 times.
  • 33 P-ATP (illuminance 0.01 ⁇ Ci/ ⁇ L final) was added to the reaction system to start the reaction.
  • kinase activity data is expressed as the ratio of the kinase activity of the test well (containing the test compound) and the blank well (only containing DMSO), and the IC 50 value is obtained by curve fitting with Prism4 software (GraphPad). The experimental results are shown in Table 7.
  • BGJ-398 was purchased from Glpbio, catalog number GC10055.
  • the compound A of the present invention can significantly inhibit the activity of FGFR1-4 mutant kinase, and the effect is better than that of the reference compounds TAS-120 and BGJ-398.
  • Example 4 Evaluation of the proliferation inhibitory activity of human gastric cancer cells, bladder cancer cells and liver cancer cells
  • SNU-16 human gastric cancer cells
  • FGFR2 gastric cancer cells
  • RT112/84 human bladder cancer cells with high FGFR3 expression and FGFR3-TACC3 fusion
  • Hep3B human liver cancer cells
  • the medium of SNU-16 is PRMI-1640 medium (Invitrogen, catalog number 11875093) supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin solution, Hep3B cells and RT112/84 cells.
  • the medium is an EMEM medium (ATCC, catalog number: 30-2003) supplemented with a final concentration of 10% fetal bovine serum and a 1% penicillin/streptomycin solution.
  • Test procedure Digest the SNU-16, RT112/84 and Hep3B cells that have reached 80% cell fusion with trypsin, centrifuge and resuspend the count, and use the culture medium to make 100,000, 20,000 and 70,000 cells/mL SNU-16, RT112/84 and Hep3B cell suspension were added to a 96-well cell culture plate (90 ⁇ L/well) and placed in a cell culture incubator containing 5% CO 2 at 37°C. After the cells were cultured for 24 hours, the reference compound Epirubicin and the test compound A were dissolved in DMSO into a mother liquor with a concentration of 30 mM.
  • the final concentration of the test compound is 30 ⁇ M (as IC50 test The initial concentration), 5 times decreasing dilution 9 concentrations, 9 concentrations are: 30 ⁇ M, 6 ⁇ M, 1.2 ⁇ M, 0.24 ⁇ M, 0.048 ⁇ M, 0.0096 ⁇ M, 0.0019 ⁇ M, 0.0004 ⁇ M and 0.00008 ⁇ M, mix and centrifuge, set Cultured in a cell incubator containing 5% CO 2 at 37°C for 3 days.
  • Table 8 The inhibitory effect of compound A on the proliferation of SNU-16, RT112/84 and Hep3B cells (IC 50 , nM)
  • Epirubicin was purchased from TOCRIS, article number 3260, batch number 2A7193516.
  • Compound A has a significant inhibitory effect on the proliferation of tested SNU-16, RT112/84 and Hep3B cells. It can be seen that compound A has a significant inhibitory effect on the proliferation of tumor cells with abnormal FGFR expression, and the effect is better than that of the reference compound. Spectrum anticancer drug Epirubicin.
  • Example 5 Evaluation of inhibitory activity on the proliferation of human cholangiocarcinoma cells
  • the MTT method was used to determine the inhibitory effect of test compound A on the proliferation of human cholangiocarcinoma cells HuCCT1 with high FGFR2 expression and human intrahepatic cholangiocarcinoma cells RBE.
  • the cell culture medium used was PRMI-1640 medium (Gibco, lot number: 8119264) supplemented with fetal bovine serum at a final concentration of 10%.
  • Test procedure Inoculate a certain number of cells in logarithmic growth phase in a 96-well plate (100 ⁇ L/well), and add 100 ⁇ L of culture medium containing different concentration gradients of compound A or the control drug TAS-120 to each well after 24 hours of attachment. There are 3 multiple holes for each drug concentration, and corresponding blank holes (only medium) and normal holes (drug concentration is 0). After 72 hours of drug action, add MTT working solution (5mg/mL, 20 ⁇ L per well), act at 37°C for 4 hours, shake the plate to remove the supernatant, add 150 ⁇ L of DMSO (analytical purity); Wipe the plate clean, and detect the optical density (OD) at 550nm with a microplate reader.
  • MTT working solution 5mg/mL, 20 ⁇ L per well
  • Inhibition rate (%) ( normal OD value-OD value dosing hole ) / ( normal OD value-OD value blank hole ) ⁇ 100%
  • Compound A has a good inhibitory effect on the proliferation of HuCCT1 and RBE cells tested, while TAS-120 has almost no inhibitory effect on the proliferation of HuCCT1 and RBE cells, with significant differences.
  • Example 6 In vivo pharmacodynamic evaluation of human gastric cancer SNU-16 cell subcutaneous xenograft tumor BALB/c nude mouse model
  • the BALB/c nude mouse model of human gastric cancer SNU-16 xenograft tumors amplified by FGFR2 gene was used to determine the inhibitory effect of compound A on human gastric cancer.
  • SNU-16 cells were cultured in vitro under RPMI-1640 medium containing 10% fetal bovine serum and 2mM L-glutamine, cultured in an incubator containing 5% CO 2 at 37°C. Use pancreatin-EDTA for routine digestion and passage twice a week. When the cell saturation is 80%-90% and the number reaches the requirement, the cells are collected, counted, and the test is carried out according to the following steps.
  • the reference compound TAS-120 and the test compound A are dissolved in an aqueous solution containing 0.5% (w/v) methyl cellulose (MC) and 0.5% (v/v) Tween 80 into an appropriate solution, and administered at 10 mL/kg Volumetric gavage was given to mice for 28 consecutive days.
  • the tumor diameter was measured with vernier calipers twice a week.
  • TGI tumor growth inhibition rate
  • Example 7 In vivo pharmacodynamic evaluation of human bladder cancer RT112/84 cell subcutaneous xenograft tumor BALB/c nude mouse model
  • RT112/84 cells were cultured in a monolayer in vitro, and the culture conditions were EMEM medium (Gibco, catalog number 11140076) containing 10% fetal bovine serum, 1% NEAA (non-essential amino acids), and 2mM L-glutamine (Gibco, catalog number 11140076). Cultivation in an incubator containing 5% CO 2. Use pancreatin-EDTA for routine digestion and passage twice a week. When the cell saturation is 80%-90% and the number reaches the requirement, the cells are collected, counted, and the test is carried out according to the following steps.
  • the control compound TAS-120 and the test compound A were dissolved into an appropriate solution with an aqueous solution containing 0.5% (w/v) MC and 0.5% (v/v) Tween 80, and were administered to mice by gavage at a dose volume of 10 mL/kg , Continuous administration for 20 days.
  • the tumor diameter was measured with vernier calipers twice a week.
  • TGI tumor growth inhibition rate
  • Example 8 In vivo pharmacodynamic evaluation of human liver cancer LI-03-0332 subcutaneous xenograft model
  • a subcutaneous xenograft tumor model constructed by nude mice after inoculation with LI-03-0332 human liver cancer tissue with high expression of FGFR3 was used to determine the inhibitory effect of compound A on human liver cancer.
  • Tumor tissue The LI-03-0332 model of human liver cancer was originally established from clinical samples resected by surgery. The collection and use of specimens strictly abide by national, hospital and company-related ethical laws and regulations. The passage naming rule is: the tumor sample is inoculated into nude mice as the P0 generation, and the subsequent passage is the P1 generation, and so on, the recovered sample is named FP, and the tumor tissue used in this experiment is the FP9 generation.
  • Test procedure The LI-03-0332 tumor tissue was cut into 20-30mm 3 pieces after removing the necrotic tissue. After adding base glue, the liver cancer tumor tissue was subcutaneously inoculated on the right back of each mouse, a total of 149 mice were inoculated Mice. On the 22nd day after inoculation, when the measured average tumor volume reached 135mm 3 , random stratified grouping was used according to tumor volume and animal body weight. There were 6 mice in the solvent control group and 8 mice in each of the remaining groups.
  • the control compound TAS-120 and the test compound A were dissolved into an appropriate solution with an aqueous solution containing 0.5% (w/v) MC and 0.5% (v/v) Tween 80, and were administered to mice by gavage at a dose volume of 10 mL/kg , Continuous administration for 21 days.
  • the tumor diameter was measured with vernier calipers twice a week.
  • TGI tumor growth inhibition rate
  • Table 12 Effect of compound A on tumor volume (mean ⁇ SEM, mm 3 ) of LI-03-0332 xenograft tumor model
  • the solvent control group contains 6 animals, and the other groups contain 8 animals.
  • Test procedure Take an appropriate amount of 50 times working solution of test compound A (100% DMSO dissolved) into the test hole (the final concentration of compound A is 0.1 ⁇ M), then add the mixed solution of kinase and substrate; add the selected The concentration of ATP solution starts to react; the mixture of kinase and substrate and compound do not need to be pre-incubated before ATP is added.
  • the Functional Observation Combination Test was used to evaluate the effect of single intragastric administration of test compound A on the central nervous system function of SD rats. Divide 20 male and female rats into 4 groups, each of which has 5 male and female rats. Orally administered a vehicle (containing 0.5% (weight/volume, w/v) methylcellulose and 0.2% (w/v) Tween 80). Aqueous solution) or compound A at doses of 0.5, 1.2 and 3 mg/kg. The administration volume for all animals was 5 mL/kg. In this experiment, animals were observed for mortality and weighed. FOB observations were performed before the test, 2 hours after the administration, 8 hours after the administration, and 24 hours after the administration. Observation indicators include motor function, behavior change, coordination function, sensory/motor reflex and body temperature. As a result, no changes related to the test article were seen at each observation time point. Under the test conditions, there was no effect of test compound A on the central nervous system of rats.
  • test compound A Using telemetry, the effects of oral administration of test compound A on the cardiovascular parameters of awake beagle dogs were evaluated.
  • Female and male dogs were orally administered a control formulation (vehicle: an aqueous solution containing 0.5% (w/v) methylcellulose and 0.2% (w/v) Tween 80), and the test compound at a dose of 0.3, 0.6 or 2 mg/kg A.
  • the survival rate of the animals is observed every day.
  • Cage-side observations were conducted twice a day on non-dosing days, and detailed clinical observations were performed before and after each dosing.
  • the electrocardiogram, heart rate and blood pressure of all experimental animals were continuously recorded at least 2 hours before each administration to about 24 hours after administration.
  • test compound A A single oral gavage of the test compound A was given to SD rats to evaluate its effect on respiratory function. Divide 20 female and male rats into 4 groups, each group has 5 male and female, and the control formulation (vehicle: containing 0.5% (w/v) methyl cellulose and 0.2% (w/v) Tween 80 aqueous solution) was administered orally. Or 0.5, 1.2 or 3 mg/kg of test compound A. The administration volume for all animals was 5 mL/kg. Before administration, about 15 minutes of respiratory data (tidal volume, respiratory rate, ventilation volume per minute) were collected as the baseline of respiratory parameters before grouping.
  • the collection time points on the day of administration were before the administration, 2 hours after the administration, 8 hours after the administration, and 24 hours after the administration, and collected data for approximately 15 minutes.
  • the results showed that 24 hours after a single oral administration, the test article had no effect on the rat's respiratory rate, tidal volume and minute ventilation.
  • Example 11 Acute toxicity test
  • Test method 40 rats were randomly divided into 4 groups, 10 rats in each group, half male and half male, and compound A and the control solvent were administered by oral gavage.
  • the dose of compound A was 10, 40 or 400 mg/kg, respectively.
  • the solvent is an aqueous solution containing 0.5% (w/v) MC and 0.2% (w/v) Tween 80 to detect the maximum tolerated dose of compound A.
  • the administration volume is 10 mL/kg, and the observation period is 14 days.
  • Test results Only in the 400mg/kg dose group, abnormal yellow stools and a slight increase in total bilirubin were observed. There were no deaths, clinical symptoms, gross lesions, weight changes, food intake, and clinical tests (hematology, blood coagulation, serum biochemistry, urinalysis) related to the test product in the female and male animals in the other dose groups compared with the solvent control group. difference. Therefore, the maximum tolerated dose (MTD) for a single administration under the experimental conditions is 400 mg/kg.
  • MTD maximum tolerated dose
  • Test method 8 beagle dogs were randomly divided into 4 groups, 2 dogs in each group, half male and half male, and compound A and the control solvent were given by oral gavage.
  • the dose of compound A was 15, 50 or 250 mg/ kg
  • the solvent is an aqueous solution containing 0.5% (w/v) MC and 0.2% (w/v) Tween 80.
  • the administration volume is 5mL/kg.
  • the animals were fasted overnight before dosing. The observation period is 14 days. Both males and females undergo necropsy on the 21st day.
  • Test results A single dose of 15, 50, or 250 mg/kg of compound A was administered to beagle dogs. There were no mortality, clinical symptoms, body weight, food intake, hematology, blood coagulation, serum biochemistry, urine Fluid analysis parameters, gross pathological changes, and histopathological adverse reactions. Therefore, it is believed that the maximum tolerable dose (MTD) of male and female beagle dogs under this test condition is 250 mg/kg.
  • MTD tolerable dose
  • Compound A has a high tolerable dose in toxicity test of single intragastric administration and has good safety.

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Abstract

L'invention concerne l'utilisation d'un inhibiteur de FGFR. Plus spécifiquement, l'invention concerne un inhibiteur de FGFR pour traiter des tumeurs associées au FGFR ou un sel pharmaceutiquement acceptable de celui-ci, une composition pharmaceutique le comprenant, une méthode de traitement de tumeurs associées au FGFR au moyen d'un médicament le comprenant, et l'utilisation de celui-ci dans la préparation d'un médicament pour le traitement de tumeurs associées au FGFR. Des résultats de test in vitro et in vivo montrent que le composé A a pour effet d'inhiber l'activité de tumeurs du système digestif ou urinaire associées à une expression anormale du FGFR, peut être utilisé pour développer un médicament pour le traitement de maladies impliquant des tumeurs du système digestif ou urinaire, et présente des valeurs d'application clinique importantes.
PCT/CN2020/127211 2019-11-08 2020-11-06 Utilisation d'un inhibiteur de fgfr Ceased WO2021089005A1 (fr)

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WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
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WO2025265060A1 (fr) 2024-06-21 2025-12-26 Revolution Medicines, Inc. Compositions thérapeutiques et procédés de gestion d'effets liés au traitement
WO2026006747A1 (fr) 2024-06-28 2026-01-02 Revolution Medicines, Inc. Inhibiteurs de ras
WO2026015790A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble lié à ras
WO2026015796A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble lié à ras
WO2026015825A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Utilisation d'un inhibiteur de ras pour traiter le cancer du pancréas
WO2026015801A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble liés à ras

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023232012A1 (fr) * 2022-05-30 2023-12-07 石药集团中奇制药技术（石家庄）有限公司 Association pharmaceutique et composition pharmaceutique pour le traitement du cancer
WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras
WO2025265060A1 (fr) 2024-06-21 2025-12-26 Revolution Medicines, Inc. Compositions thérapeutiques et procédés de gestion d'effets liés au traitement
WO2026006747A1 (fr) 2024-06-28 2026-01-02 Revolution Medicines, Inc. Inhibiteurs de ras
WO2026015790A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble lié à ras
WO2026015796A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble lié à ras
WO2026015825A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Utilisation d'un inhibiteur de ras pour traiter le cancer du pancréas
WO2026015801A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble liés à ras

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