CN114641293B - Application of FGFR inhibitor - Google Patents
Application of FGFR inhibitor Download PDFInfo
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- CN114641293B CN114641293B CN202080076195.1A CN202080076195A CN114641293B CN 114641293 B CN114641293 B CN 114641293B CN 202080076195 A CN202080076195 A CN 202080076195A CN 114641293 B CN114641293 B CN 114641293B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Use of FGFR inhibitor is provided. More specifically, an FGFR inhibitor or a pharmaceutically acceptable salt thereof for treating an FGFR-related tumor, a pharmaceutical composition comprising the same, a method of treating an FGFR-related tumor using a medicament containing the same, and the use thereof in preparing a medicament for treating an FGFR-related tumor. In vitro and in vivo test results show that the compound A has the activity of inhibiting digestive or urinary system tumor related to FGFR abnormal expression, can be used for developing medicaments for treating digestive or urinary system tumor diseases, and has important clinical application value.
Description
Cross Reference to Related Applications
The present application claims priority from chinese patent application number 201911086889.9 filed on 8 of 11 in 2019 and chinese patent application number 202010321669.6 filed on 22 of 4 in 2020, both of which are hereby incorporated by reference in their entireties.
Technical Field
The invention belongs to the field of medicines. More particularly, the present invention relates to an FGFR inhibitor or a pharmaceutically acceptable salt thereof for treating an FGFR-associated tumor, a pharmaceutical composition comprising the same, a method of treating an FGFR-associated tumor using a medicament containing the same, and the use thereof in the preparation of a medicament for treating an FGFR-associated tumor.
Background
Fibroblast growth factor receptor (fibroblast growth factor receptor, FGFR) is a receptor for fibroblast growth factor (fibroblast growth factor, FGF) signaling, the family of which consists of four members (FGFR 1-4). FGF plays an important role in many physiological regulatory processes such as cell proliferation, cell differentiation, cell migration, and angiogenesis through FGFR. Many studies have shown that abnormalities in FGF signaling pathway (high expression, gene amplification, gene mutation, chromosomal recombination, etc.) are directly associated with many pathological processes such as tumor cell proliferation, migration, invasion, and angiogenesis, and that FGFR exhibits overexpression or overactivation in various tumors such as non-small cell lung cancer, breast cancer, gastric cancer, bladder cancer, urothelial cancer, endometrial cancer, liver cancer, prostate cancer, cervical cancer, colon cancer, esophageal cancer, myeloma, etc. For example, FGFR2 fusion mutations were found to occur in about 10-20% of intrahepatic cholangiocarcinoma patients; the change of FGFR3 gene has stronger correlation with pathological low-grade and clinical low-grade cancers in bladder cancer, and more than 70 percent of pathological low-grade non-invasive urothelial papillomas contain FGFR3 mutation; and FGFR1, FGFR2 and FGFR3 are found to be highly expressed in both stomach cancer tissues and stomach cancer cells. Therefore, FGFR becomes an important therapeutic target, attracting extensive research and development interest.
Inhibitors targeting the kinase domain within the FGFR membrane can be classified into ATP-competitive inhibitors, non-ATP-competitive reversible inhibitors and irreversible inhibitors according to the mechanism of action, wherein the inhibitory activity of the non-ATP-competitive reversible inhibitors and irreversible inhibitors on the kinase is not affected by high ATP concentrations in cells and in vivo. In recent years, some medicines targeting FGFR for treating the above-mentioned tumor diseases have entered clinical trial stages, such as Balversa (erdastinib, erdafitinib) as a panfgfr reversible inhibitor targeting medicine for metastatic urothelial cancer approved by the FDA for the first time worldwide. In addition, other FGFR1-4 inhibitors (e.g., BGJ-398, debio-1347, TAS-120, etc.) are currently in different clinical phase trials of solid tumors such as urothelial carcinoma, liver cancer, etc. The structural formula of the medicine is as follows:
However, it was found that reversible inhibitors of pan-FGFR (pan-FGFR) such as BGJ-398 inevitably develop resistance after 4-6 months of use, resulting in reduced efficacy, while irreversible inhibitors such as TAS-120 remain effective for patients after BGJ-398 resistance, exhibiting the unique advantages of irreversible inhibitors. However, no irreversible FGFR1-4 inhibitor has been approved for use in the market at home and abroad.
Primary liver cancer (abbreviated as liver cancer) is a relatively common malignant tumor, is the cause of cancer death caused by the 4 th major factor worldwide, and causes serious threat to the life health of human beings. Liver cancer mainly includes hepatocellular carcinoma (hepatocellular carcinoma, HCC), intrahepatic cholangiocarcinoma (INTRAHEPATIC CHOLANGIOCARCINOMA, ICC), and mixed liver cancer (combined hepatocellular cholangiocarcinoma, c-CC). Liver cancer has no obvious clinical symptoms in early stage, and is found to be in middle and late stage frequently, and has the advantages of large malignancy degree, high recurrence rate, poor treatment effect and poor prognosis. The means for clinically treating liver cancer mainly comprises methods of operation treatment, chemoembolization by hepatic artery (TRANSCATHETER ARTERIAL chemoembolization, TACE), chemoradiotherapy and the like. However, residual liver tissue from post-operative patients remains at risk for cancer, with a 5-year recurrence risk of over 70%. Sorafenib (Sorafenib) is currently the only molecular targeted drug approved for the treatment of advanced liver cancer, but its efficacy on liver cancer patients with liver function Child-Pugh graded to B-grade remains poor.
Urothelial cancer (urothelial cancer, UCC) is a common malignancy worldwide, and is also one of the most common malignancies in urologic clinics in our country, with 90% -95% of urothelial cancers being bladder cancers. The initial diagnosis of urothelial cell carcinoma is mostly non-myogenic invasive, but has high recurrence rate; and with the increase of recurrence times, the malignancy of the tumor increases and turns into myometrial invasive tumor. Patients with metastatic urothelial cancer with FGFR gene changes have poor prognosis and low response rate to treatment, and there is a significant clinical need far from being met in this class of patients. For decades, the standard of treatment for urothelial cancer has been a Cisplatin (CISPLATIN) -based chemotherapy regimen. The efficacy of the two-wire chemotherapy drug vinflunine (Vinflunine) or taxane (taxanes) is slightly improved, the historical objective remission rate (objective response rate, ORR) is only about 10%, and the median total survival (OS) is 7-9 months. Advanced or metastatic urothelial cancer also has an overall response rate of only 15% to 20% for recently approved PD-1/PD-L1 checkpoint inhibitors, with a median OS of about 10 months, and many patients do not benefit.
Gastric cancer (GASTRIC CANCER) is also one of the common malignant tumors worldwide, and has relatively poor prognosis, seriously threatening human health. Because of the lack of a mature early screening system, atypical early gastric cancer symptoms and low discovery rates, most patients are diagnosed as advanced. The current therapeutic measures against gastric cancer mainly comprise surgical treatment, systemic application of chemical drugs, radiotherapy and molecular targeted drug treatment. The targeting therapy is drug therapy aiming at specific targets of tumors, but clinical researches on the targeting therapy of gastric cancer are less successful and more failed due to the reasons of strong heterogeneity of gastric cancer and the like.
Cholangiocarcinoma (cholangiocarcinoma, CCA) is an epithelial cell malignancy with different cholangiocellular differentiation characteristics, increasing incidence by nearly 20% over the last 10 years, accounting for about 3% of gut tumors and 10-15% of hepatobiliary malignancies. Bile duct cancers can be classified into intrahepatic bile duct cancers and extrahepatic bile duct cancers (extrahepatic cholangiocarcinoma, eCCA), the latter further classified into portal bile duct cancers (PERIHILAR CHOLANGIOCARCINOMA, pCCA) and distal bile duct cancers (distal cholangiocarcinoma, dCCA), depending on anatomical location. Radical surgery is the only cure, but there is no characteristic clinical manifestation in the early stages of the disease, and about 2/3 of patients have lost surgical opportunities at the time of initial diagnosis, with a survival rate of about 10% in 5 years. Even with surgical excision, the recurrence rate after bile duct cancer surgery is as high as 50% for 1 year. For unresectable local advanced stages, i.e., metastatic biliary tract tumors (including intrahepatic and extrahepatic cholangiocarcinomas, gall bladder cancers, i.e., ampullate cancers, etc.), standard first-line chemotherapy regimens (gemcitabine in combination with cisplatin) only lead to median survival of 11.7 months with very poor prognosis. However, FGFR inhibitor has shown promise in clinical trials of bile duct cancer, for example, FGFR inhibitor BGJ-398 obtains excellent phase II trial results in the progressive stage of FGFR gene fusion, mutation, amplification, and objective remission rate and disease control rate reach 18.8% and 83.3% in FGFR gene fusion patients.
Intrahepatic cholangiocarcinoma refers to malignant tumors from bile duct epithelium located in the second and above stages of the liver, also called intrahepatic cholangiocarcinoma, which is one of primary liver cancers (10% -15%), and can be attributed to one of cholangiocarcinomas (about 10%) depending on the site of occurrence. The intrahepatic cholangiocarcinoma has high malignancy, strong invasion and lymph node metastasis characteristics, difficult early diagnosis, poor prognosis of patients, overall survival rate of less than 10% in 5 years, and median survival time of 36 months after surgical excision. The only method for curing the intrahepatic cholangiocarcinoma at present is still early detection and surgical excision, but the recurrence rate after excision is also high. Patients who are not resectable and relapsing and metastasizing at a locally advanced stage are even lacking effective measures to significantly improve prognosis. Intrahepatic cholangiocarcinoma is insensitive to traditional chemotherapy, radiotherapy and recent tumor immunotherapy, and no standard treatment method exists for cholangiocarcinoma patients who fail to undergo gemcitabine chemotherapy as a first-line drug. The literature reports that patients receiving various regimens of two-line chemotherapy of 5-fluorouracil (5-FU) and irinotecan, 5-FU and oxaliplatin, 5-FU and cisplatin, 5-FU or capecitabine and sunitinib, have median 3.2 and 6.7 months of disease progression-free survival (PFS) and total survival (OS), respectively, with no significant difference in PFS or OS between each regimen. There have been many reports on the study of the molecular mechanism of intrahepatic cholangiocarcinoma. Nakamura et al performed a comprehensive genomic analysis of 260 cholangiocarcinoma patients, and found that 40% of cases exhibited changes in the FGFR gene, with FGFR2 exhibiting high expression in intrahepatic cholangiocarcinoma. Using the second generation sequencing technique, it was also found that 13% -50% of intrahepatic cholangiocarcinoma patients carried FGFR2 gene fusions, with 13.6% of patients containing FGFR2-BICC1 and FGFR2-AHCYL1 gene fusions. These findings provide new opportunities for the treatment of intrahepatic cholangiocarcinoma.
Currently, several FGFR inhibitors are currently 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), etc., and the FGFR inhibitor used in cholangiocarcinoma was originally reported to be BGJ-398. Studies report that 3 patients with FGFR2 fusion positive intrahepatic bile duct cancer treated with BGJ-398 developed clinically acquired FGFR inhibitor resistance, and further studies found polyclonal secondary mutations in the FGFR2 kinase domain, including FGFR 2V 564F gene mutations that were present in all 3 patients. TAS-120 is a highly selective irreversible pan FGFR inhibitor. The study shows that TAS-120 has clinical effect on BGJ-398 resistant patients with intrahepatic cholangiocarcinoma and can inhibit the secondary mutation of a plurality of FGFR 2. However, there is no document disclosing data on the inhibitory activity of the cellular level of TAS-120. At present, no targeted medicine for treating intrahepatic cholangiocarcinoma is available in the market.
WO2019034076A1 discloses FGFR inhibitors and their pharmaceutical use, including compound a (example 2). This patent application discloses the results of in vitro inhibition activity evaluation of FGFR wild-type kinase by compound a, the results of in vitro inhibition activity evaluation of mutant kinase and the results of pharmacokinetic evaluation in mice, but does not disclose which diseases compound a is specifically useful for treatment.
Disclosure of Invention
[ Object of the invention ]
An object of the present invention is to provide a use of a Fibroblast Growth Factor Receptor (FGFR) inhibitor compound a or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating FGFR-associated tumors.
It is another object of the present invention to provide an FGFR inhibitor compound a or a pharmaceutically acceptable salt thereof for treating FGFR-associated tumors.
It is another object of the present invention to provide a method of treating FGFR-associated tumors comprising administering to a subject or patient a medicament comprising a therapeutically effective amount of one FGFR inhibitor compound a or a pharmaceutically acceptable salt thereof.
It is a further object of the present invention to provide a pharmaceutical composition for treating FGFR-associated tumors comprising an FGFR inhibitor compound a or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier.
[ Solution ] according to the present invention
The invention aims to provide a small molecular compound with excellent FGFR1-4 wild type and mutant kinase inhibition activity, and a pharmaceutical composition, application and treatment method thereof.
Another technical problem to be solved by the present invention is to provide a small molecule compound having excellent FGFR1-4 wild-type and mutant kinase inhibitory activity and excellent in vitro/in vivo activity against FGFR-related tumors (particularly digestive or urinary system tumors), and pharmaceutical compositions, uses and therapeutic methods thereof.
Still another technical problem to be solved by the present invention is to provide a small molecular compound having excellent FGFR1-4 wild-type and mutant kinase inhibitory activity and excellent in vitro/in vivo anti-FGFR-associated tumor (especially digestive or urinary system tumor) activity, and having excellent safety, and a pharmaceutical composition, use and therapeutic method thereof.
Still another technical problem to be solved by the present invention is to provide a small molecular compound having excellent FGFR1-4 wild-type and mutant kinase inhibitory activity and excellent in vitro/in vivo anti-FGFR-associated tumor (especially digestive or urinary system tumor) activity, and having excellent plasma stability and safety, and a pharmaceutical composition, use and therapeutic method thereof.
In order to solve the technical problems, the inventor of the application carries out further experiments on the basis of the prior art WO2019034076A1, and discovers that the compound A has good inhibitory activity on wild type FGFR1-4 and mutant FGFR1-4, can obviously inhibit the proliferation of digestive or urinary tumor cells and xenograft tumor models related to the abnormal expression of FGFR1-4, and has higher plasma stability and safety, thereby suggesting that the compound A can be used for developing medicaments for treating digestive or urinary tumor diseases related to FGFR. The results of these studies have led to completion of the technical solution of the present application.
Specifically, in a first aspect of the present invention, there is provided the use of an FGFR inhibitor compound a or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of FGFR-associated tumors, wherein the compound a has the structure:
In one embodiment, the FGFR-associated tumor is one or more of a digestive or urinary system tumor.
In one embodiment, the FGFR-associated tumor is any one of gastric cancer, liver cancer, urothelial cancer, cholangiocarcinoma, or any combination thereof.
In one embodiment, the FGFR-associated tumor is gastric cancer. In a preferred embodiment, the gastric cancer is FGFR2 gene amplified gastric cancer.
In one embodiment, the FGFR-associated tumor is liver cancer. In a preferred embodiment, the liver cancer is a liver cancer with high FGFR4/FGF19 expression. In a preferred embodiment, the liver cancer is a liver cancer with high FGFR3 expression. In a preferred embodiment, the liver cancer is any one of hepatocellular carcinoma, intrahepatic cholangiocarcinoma, mixed liver cancer, or any combination thereof.
In one embodiment, the FGFR-associated tumor is urothelial cancer. In a preferred embodiment, the urothelial cancer is bladder cancer. In a preferred embodiment, the bladder cancer is one in which FGFR3 is highly expressed and FGFR3-TACC3 is fused.
In one embodiment, the FGFR-associated tumor is cholangiocarcinoma. In a preferred embodiment, the cholangiocarcinoma is that of FGFR2 with high expression. In a preferred embodiment, the bile duct cancer is any one of intrahepatic bile duct cancer, portal bile duct cancer, distal bile duct cancer, or any combination thereof. In a more preferred embodiment, the cholangiocarcinoma is intrahepatic cholangiocarcinoma.
In one embodiment, the compound a or a pharmaceutically acceptable salt thereof is the only active ingredient in the medicament.
In one embodiment, the compound a or a pharmaceutically acceptable salt thereof is used in combination with one or more other targeted or chemotherapeutic agents.
In one embodiment, the medicament is formulated into a clinically acceptable formulation. In a preferred embodiment, the formulation is an oral formulation, an injectable formulation or an external formulation.
In one embodiment, the compound a or a pharmaceutically acceptable salt thereof is administered in a daily dosage range from about 0.001mg/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 0.01mg/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 0.02mg/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 0.03mg/kg to about 20 mg/kg.
In one embodiment, the medicament contains a therapeutically effective amount of compound a or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the therapeutically effective amount is 0.001-1000mg. In a preferred embodiment, the therapeutically effective amount is 0.01-100mg. In a preferred embodiment, the therapeutically effective amount is 0.1-50mg. In a preferred embodiment, the therapeutically effective amount is 0.5-30mg.
In one embodiment, the compound a or a pharmaceutically acceptable salt thereof is administered in a single dose or in divided doses.
In one embodiment, the drug is administered orally, by injection, topically or in vitro. In a preferred embodiment, the medicament is administered orally or by injection.
In a second aspect of the invention, there is provided an FGFR inhibitor compound a or a pharmaceutically acceptable salt thereof for use in the treatment of FGFR-associated tumors, wherein the compound a has the structure:
In one embodiment, the FGFR-associated tumor is one or more of a digestive or urinary system tumor.
In one embodiment, the FGFR-associated tumor is any one of gastric cancer, liver cancer, urothelial cancer, cholangiocarcinoma, or any combination thereof.
In one embodiment, the FGFR-associated tumor is gastric cancer. In a preferred embodiment, the gastric cancer is FGFR2 gene amplified gastric cancer.
In one embodiment, the FGFR-associated tumor is liver cancer. In a preferred embodiment, the liver cancer is a liver cancer with high FGFR4/FGF19 expression. In a preferred embodiment, the liver cancer is a liver cancer with high FGFR3 expression. In a preferred embodiment, the liver cancer is any one of hepatocellular carcinoma, intrahepatic cholangiocarcinoma, mixed liver cancer, or any combination thereof.
In one embodiment, the FGFR-associated tumor is urothelial cancer. In a preferred embodiment, the urothelial cancer is bladder cancer. In a preferred embodiment, the bladder cancer is one in which FGFR3 is highly expressed and FGFR3-TACC3 is fused.
In one embodiment, the FGFR-associated tumor is cholangiocarcinoma. In a preferred embodiment, the cholangiocarcinoma is that of FGFR2 with high expression. In a preferred embodiment, the bile duct cancer is any one of intrahepatic bile duct cancer, portal bile duct cancer, distal bile duct cancer, or any combination thereof. In a more preferred embodiment, the cholangiocarcinoma is intrahepatic cholangiocarcinoma.
In one embodiment, the compound a or a pharmaceutically acceptable salt thereof is used as the sole active ingredient.
In one embodiment, the compound a or a pharmaceutically acceptable salt thereof is used in combination with one or more other targeted or chemotherapeutic agents.
In one embodiment, the compound a or a pharmaceutically acceptable salt thereof is formulated into a clinically acceptable formulation. In a preferred embodiment, the formulation is an oral formulation, an injectable formulation or an external formulation.
In one embodiment, the compound a or a pharmaceutically acceptable salt thereof is administered in a daily dosage range from about 0.001mg/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 0.01mg/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 0.02mg/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 0.03mg/kg to about 20 mg/kg.
In one embodiment, the compound a or a pharmaceutically acceptable salt thereof is formulated in a medicament in a therapeutically effective amount. In a preferred embodiment, the therapeutically effective amount is 0.001-1000mg. In a preferred embodiment, the therapeutically effective amount is 0.01-100mg. In a preferred embodiment, the therapeutically effective amount is 0.1-50mg. In a preferred embodiment, the therapeutically effective amount is 0.5-30mg.
In one embodiment, the compound a or a pharmaceutically acceptable salt thereof is administered in a single dose or in divided doses.
In one embodiment, the compound a or a pharmaceutically acceptable salt thereof is administered orally, by injection, topically or in vitro. In a preferred embodiment, the compound a or a pharmaceutically acceptable salt thereof is administered by oral administration or injection.
In a third aspect of the invention, there is provided a method of treating a FGFR-associated tumor comprising administering to a subject or patient a medicament comprising a therapeutically effective amount of an FGFR inhibitor compound a or a pharmaceutically acceptable salt thereof, wherein compound a has the structure:
In one embodiment, the FGFR-associated tumor is one or more of a digestive or urinary system tumor.
In one embodiment, the FGFR-associated tumor is any one of gastric cancer, liver cancer, urothelial cancer, cholangiocarcinoma, or any combination thereof.
In one embodiment, the FGFR-associated tumor is gastric cancer. In a preferred embodiment, the gastric cancer is FGFR2 gene amplified gastric cancer.
In one embodiment, the FGFR-associated tumor is liver cancer. In a preferred embodiment, the liver cancer is a liver cancer with high FGFR4/FGF19 expression. In a preferred embodiment, the liver cancer is a liver cancer with high FGFR3 expression. In a preferred embodiment, the liver cancer is any one of hepatocellular carcinoma, intrahepatic cholangiocarcinoma, mixed liver cancer, or any combination thereof.
In one embodiment, the FGFR-associated tumor is urothelial cancer. In a preferred embodiment, the urothelial cancer is bladder cancer. In a preferred embodiment, the bladder cancer is one in which FGFR3 is highly expressed and FGFR3-TACC3 is fused.
In one embodiment, the FGFR-associated tumor is cholangiocarcinoma. In a preferred embodiment, the cholangiocarcinoma is that of FGFR2 with high expression. In a preferred embodiment, the bile duct cancer is any one of intrahepatic bile duct cancer, portal bile duct cancer, distal bile duct cancer, or any combination thereof. In a more preferred embodiment, the cholangiocarcinoma is intrahepatic cholangiocarcinoma.
In one embodiment, the compound a or a pharmaceutically acceptable salt thereof is administered as the sole active ingredient.
In one embodiment, the compound a or a pharmaceutically acceptable salt thereof is administered in combination with one or more other targeted or chemotherapeutic agents.
In one embodiment, the medicament is formulated into a clinically acceptable formulation. In a preferred embodiment, the formulation is an oral formulation, an injectable formulation or an external formulation.
In one embodiment, the compound a or a pharmaceutically acceptable salt thereof is administered in a daily dosage range from about 0.001mg/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 0.01mg/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 0.02mg/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 0.03mg/kg to about 20 mg/kg.
In one embodiment, the therapeutically effective amount is 0.001-1000mg. In a preferred embodiment, the therapeutically effective amount is 0.01-100mg. In a preferred embodiment, the therapeutically effective amount is 0.1-50mg. In a preferred embodiment, the therapeutically effective amount is 0.5-30mg.
In one embodiment, the compound a or a pharmaceutically acceptable salt thereof is administered in a single dose or in divided doses.
In one embodiment, the compound a or a pharmaceutically acceptable salt thereof is administered orally, by injection, topically or in vitro. In a preferred embodiment, the compound a or a pharmaceutically acceptable salt thereof is administered by oral administration or injection.
In a fourth aspect of the invention, there is provided a pharmaceutical composition for use in the treatment of FGFR-associated tumors comprising an FGFR inhibitor compound a or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier, wherein the compound a has the structure:
In one embodiment, the FGFR-associated tumor is one or more of a digestive or urinary system tumor.
In one embodiment, the FGFR-associated tumor is any one of gastric cancer, liver cancer, urothelial cancer, cholangiocarcinoma, or any combination thereof.
In one embodiment, the FGFR-associated tumor is gastric cancer. In a preferred embodiment, the gastric cancer is FGFR2 gene amplified gastric cancer.
In one embodiment, the FGFR-associated tumor is liver cancer. In a preferred embodiment, the liver cancer is a liver cancer with high FGFR4/FGF19 expression. In a preferred embodiment, the liver cancer is a liver cancer with high FGFR3 expression. In a preferred embodiment, the liver cancer is any one of hepatocellular carcinoma, intrahepatic cholangiocarcinoma, mixed liver cancer, or any combination thereof.
In one embodiment, the FGFR-associated tumor is urothelial cancer. In a preferred embodiment, the urothelial cancer is bladder cancer. In a preferred embodiment, the bladder cancer is one in which FGFR3 is highly expressed and FGFR3-TACC3 is fused.
In one embodiment, the FGFR-associated tumor is cholangiocarcinoma. In a preferred embodiment, the cholangiocarcinoma is that of FGFR2 with high expression. In a preferred embodiment, the bile duct cancer is any one of intrahepatic bile duct cancer, portal bile duct cancer, distal bile duct cancer, or any combination thereof. In a more preferred embodiment, the cholangiocarcinoma is intrahepatic cholangiocarcinoma.
In one embodiment, the compound a or a pharmaceutically acceptable salt thereof is the only active ingredient in the pharmaceutical composition.
In one embodiment, the pharmaceutical composition further comprises one or more other targeted or chemotherapeutic agents as an active ingredient.
In one embodiment, the pharmaceutical composition is formulated into a clinically acceptable formulation. In a preferred embodiment, the formulation is an oral formulation, an injectable formulation or an external formulation.
In one embodiment, the compound a or a pharmaceutically acceptable salt thereof is administered in a daily dosage range from about 0.001mg/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 0.01mg/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 0.02mg/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 0.03mg/kg to about 20 mg/kg.
In one embodiment, the pharmaceutical composition contains a therapeutically effective amount of compound a or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the therapeutically effective amount is 0.001-1000mg. In a preferred embodiment, the therapeutically effective amount is 0.01-100mg. In a preferred embodiment, the therapeutically effective amount is 0.1-50mg. In a preferred embodiment, the therapeutically effective amount is 0.5-30mg.
In one embodiment, the compound a or a pharmaceutically acceptable salt thereof is administered in a single dose or in divided doses.
In one embodiment, the pharmaceutical composition is administered orally, by injection, topically or in vitro. In a preferred embodiment, the pharmaceutical composition is administered orally or by injection.
The above embodiments represent exemplary embodiments of the present invention, but the present invention is not limited to the above embodiments. In addition, the technical features of the above embodiments of the present invention may be combined with each other to constitute one or more new technical solutions, which also fall within the scope of the present invention, as long as such new technical solutions are technically feasible.
[ Beneficial effects of the invention ]
To demonstrate that compound a of the present invention is an FGFR1-4 inhibitor effective against FGFR-related tumors, in particular digestive or urinary system tumors, the present invention evaluates the in vitro kinase inhibitory activity of compound a against FGFR1-4 wild-type and mutant forms and the proliferation inhibitory activity of exemplary digestive or urinary system tumor (including gastric cancer, liver cancer, bladder cancer, cholangiocarcinoma) models associated with FGFR, and further evaluates the inhibitory effect of compound a against tumor growth against several tumor xenograft models.
The results of in vitro kinase activity tests and cell tests show that the compound A has good in vitro kinase inhibition activity on FGFR1-4 wild type and mutant type; has good inhibition effect on proliferation of human gastric cancer cells (SNU-16) amplified by FGFR2 genes, human bladder cancer cells (RT 112/84) fused with FGFR3 high expression and FGFR3-TACC3, human liver cancer cells (Hep 3B) highly expressed by FGFR4/FGF19, human bile duct cancer cells HuCCT1 highly expressed by FGFR2 and human intrahepatic bile duct cancer cells RBE; has remarkable inhibiting effect on human gastric cancer SNU-16 cell subcutaneous xenograft tumor model, human bladder cancer RT112/84 cell subcutaneous xenograft tumor model and human liver cancer LI-03-0332 subcutaneous xenograft model.
In addition, in order to examine the pharmaceutical properties of compound a, the present invention measured the plasma stability of compound a in human and mouse plasma stability tests and compared with a reference compound of close structure (example 8 (S configuration) in WO2019034076 A1). Plasma stability results show that compound a has better stability in both mouse and human plasma.
Furthermore, it is known that irreversible inhibitors enhance affinity to a target through covalent bond with the target protein relative to reversible inhibitors, which is the root cause for the irreversible inhibitors to exhibit high biological activity. However, if off-target, this affinity enhancement of irreversible inhibitors will also occur on off-target targets, leading to enhanced toxic side effects as well [ see Yang Bo et al, progress of small molecule covalent inhibitor research, pharmaceutical journal, 2014, 49 (2): 158-165]. In order to worry about greater toxic and side effects possibly brought about by irreversible inhibitors, the compound A off-target effect of the compound A on various important non-target kinases is detected, and the result shows that the compound A off-target effect is lower.
Still further, in order to evaluate the safety of compound a in the body, the present invention conducted a safe pharmacological test and an acute toxicity test against dogs and mice. The result shows that the compound A has no obvious influence on each detection index and has good safety.
In summary, the inventor of the present application found through experiments that compound a has activity of selectively inhibiting FGFR1-4, has good inhibitory activity on both wild-type FGFR1-4 and mutant FGFR1-4, can significantly inhibit proliferation of digestive or urinary tumor cells and xenograft tumor models associated with abnormal expression of FGFR1-4, and has high plasma stability and safety. Therefore, the compound A has the activity of inhibiting the digestive or urinary system tumor related to the abnormal expression of FGFR, can be used for developing medicaments for treating digestive or urinary system tumor diseases, and has important clinical application value.
[ Detailed description of the invention ]
The following terms and phrases used herein are intended to have the following meanings unless otherwise indicated. A particular term or phrase, unless otherwise specifically defined, should not be construed as being ambiguous or otherwise clear, but rather should be construed in a generic sense.
"Compound A" refers to a compound having the following structure as an FGFR inhibitor:
the synthesis is described in example 2 of WO2019034076A 1.
By "pharmaceutically acceptable salts" is meant the conventional non-toxic salts formed by the reaction of compound a of the invention with an inorganic acid, an organic acid, an inorganic base or an organic base. The salts are suitable for use in contact with human and animal tissue without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, within the scope of sound medical judgment. Pharmaceutically acceptable base addition salts or acid addition salts can be obtained by contacting compound a with a sufficient amount of a non-toxic acid or base in pure solution or in a suitable inert solvent.
By "pharmaceutically acceptable carrier" is meant a carrier suitable for formulating a pharmaceutical composition of compound a or a pharmaceutically acceptable salt thereof or a clinically acceptable formulation thereof. The carrier is suitable for use in contact with human and animal tissue without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, within the scope of sound medical judgment. "FGFR" refers to a fibroblast growth factor receptor, which is a receptor for fibroblast growth factor signaling, the family of which consists of four members (FGFR 1-4). FGF plays an important role in many physiological regulatory processes such as cell proliferation, cell differentiation, cell migration, and angiogenesis through FGFR.
"FGFR-associated tumor" refers to a tumor whose occurrence or progression is closely related to the expression and activation of any one of FGFR1-4 or any combination thereof, including but not limited to gastric cancer, bladder cancer, urothelial cancer, liver cancer, cholangiocarcinoma (e.g., intrahepatic cholangiocarcinoma).
The target drug is a target drug for treating tumor-related diseases clinically, has a targeting capability, can aim an effective component or a carrier thereof at a specific target lesion site, and accumulates or releases the effective component at the site to form a relatively high concentration, thereby improving the curative effect, inhibiting toxic and side effects and reducing the damage to normal tissues and cells.
The "chemotherapeutic drug" can act on different links of growth and propagation of tumor cells, and inhibit or kill tumor cells, and is one of the main means for treating tumor.
By "clinically acceptable formulation" is meant a formulation suitable for use in contact with human and animal tissue without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, within the scope of sound medical judgment. Clinically acceptable preparations include oral preparations, injectable preparations, external preparations and the like.
According to the present invention, the dose and frequency of administration of compound a or a pharmaceutically acceptable salt thereof can be determined by conventional methods such as modeling, dose escalation studies or clinical trials and by considering factors such as the nature and severity of the disease to be treated, the age, general condition and weight of the patient, and the specific compound administered, its pharmacokinetic properties, and route of administration. Suitable daily administration amounts of compound a or a pharmaceutically acceptable salt thereof range from about 0.001mg/kg to about 1000mg/kg; preferably, from about 0.01mg/kg to about 100mg/kg; further preferably, from about 0.02mg/kg to about 50mg/kg; still more preferably, from about 0.03mg/kg to about 20mg/kg (where "kg" refers to the body weight of the subject (i.e., subject or patient)). Preferably, the daily dosage of compound a or a pharmaceutically acceptable salt thereof is 0.001mg to 1000mg, further preferably, the daily dosage of compound a or a pharmaceutically acceptable salt thereof is 0.01mg to 100mg; still more preferably, compound a or a pharmaceutically acceptable salt thereof is administered in a daily dose of 0.1-50mg; still more preferably, the daily dose of compound a or a pharmaceutically acceptable salt thereof is from 0.5 to 30mg; still further preferred, the daily dose of compound a or a pharmaceutically acceptable salt thereof 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, administered in a single dose or divided doses.
According to the present invention, the compound a or a pharmaceutically acceptable salt thereof is included in the medicament or pharmaceutical composition in a therapeutically effective amount. The therapeutically effective amount is preferably 0.001 to 1000mg, more preferably 0.01 to 100mg, still more preferably 0.1 to 50mg, still more preferably 0.5 to 30mg, administered in a single dose or in divided doses.
According to the present invention, the therapeutically effective amount, administration dose or administration dose of compound a or a pharmaceutically acceptable salt thereof is calculated as compound a.
According to the invention, the subject or patient suffering from FGFR-associated tumors may be a human or non-human mammal such as mice, rats, guinea pigs, cats, dogs, cows, horses, sheep, pigs, monkeys, etc., more preferably a human.
[ Other embodiments of the invention ]
The invention also relates to the following embodiments:
1. Use of a Fibroblast Growth Factor Receptor (FGFR) inhibitor for the manufacture of a medicament for the treatment of FGFR-associated tumors.
2. The use according to claim 1, wherein the tumor comprises gastric cancer, liver cancer, urothelial cancer.
3. The use according to claim 2, wherein the liver cancer is hepatocellular carcinoma, intrahepatic cholangiocarcinoma, or mixed liver cancer.
4. The use according to claim 2, wherein the urothelial cancer is bladder cancer.
5. The use according to any one of claims 1 to 4, wherein the inhibitor is used in combination with one or more of a targeted drug, a chemotherapeutic drug.
6. The use according to any one of claims 1 to 4, wherein the medicament is formulated into a clinically acceptable formulation, preferably an oral formulation, an injectable formulation, an external formulation.
7. The use according to any one of claims 1 to 4, wherein the inhibitor is administered in a daily dosage ranging from about 0.001mg/kg to about 1000mg/kg; preferably from about 0.01mg/kg to about 100mg/kg; the administration may be in a single dose or in divided doses.
8. The use according to any one of schemes 1 to 4, wherein the medicament contains a therapeutically effective amount of an inhibitor, preferably 0.001-1000mg; the administration may be in a single dose or in divided doses.
Further, the present invention also relates to the following embodiments:
1. use of FGFR inhibitor compound a or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of FGFR-associated tumors.
2. The use according to claim 1, wherein the tumor is cholangiocarcinoma.
3. The use according to claim 2, wherein the bile duct cancer comprises intrahepatic bile duct cancer, portal bile duct cancer, and distal bile duct cancer; preferably intrahepatic cholangiocarcinoma.
4. The use according to claim 1 or 2, wherein the medicament further comprises one or more other targeted, chemotherapeutic agents.
5. The use according to claim 1 or 2, wherein the medicament is formulated into a clinically acceptable formulation, preferably an oral formulation, an injectable formulation, an external formulation.
6. The use according to scheme 1 or 2, characterized in that the medicament contains a therapeutically effective amount of compound a or a pharmaceutically acceptable salt thereof, preferably 0.001mg to 1000mg, further preferably 0.01 to 100mg, still further preferably 0.1 to 50mg, still further preferably 0.5 to 30mg; the administration may be in a single dose or in divided doses.
7. A method of treating FGFR-associated neoplastic disease, comprising administering to a subject or patient a therapeutically effective amount of a medicament comprising compound a or a pharmaceutically acceptable salt thereof.
8. The method of claim 7, wherein the tumor is cholangiocarcinoma.
9. The method of claim 8, wherein the bile duct cancer comprises intrahepatic bile duct cancer, portal bile duct cancer, and distal bile duct cancer; preferably intrahepatic cholangiocarcinoma.
10. The method according to any one of claims 7-9, wherein the administration may be oral administration, injection administration, topical administration or in vitro administration, preferably oral administration or injection administration.
Detailed Description
For a further understanding of the present invention, specific embodiments of the invention are described in detail below in conjunction with the following examples. It should be understood that these descriptions are intended only to further illustrate the features and advantages of the present invention, and are not to be construed as limiting the aspects of the invention.
Example 1: in vitro inhibition Activity evaluation of FGFR1-4 wild-type kinase
The inhibition of each wild type FGFR kinase by test compound A was determined by 33 P-ATP membrane filtration experiments.
Buffer conditions: 20mM 4- (2-hydroxyethyl) -1-piperazine ethanesulfonic acid (Hepes) (pH 7.5), 10mM MgCl 2, 1mM EGTA,0.02% (v/v%) benzyl 35 (Brij 35), 0.02mg/mL BSA,0.1mM Na 3VO4, 2mM DTT,1% (v/v%) DMSO.
The test steps are as follows: test compounds were dissolved in DMSO at room temperature to prepare 10mM solutions for use. The substrate (see Table 1) was added to the freshly prepared reaction buffer, and the specific kinase (see Table 2) was added to the substrate solution and gently mixed. Compounds dissolved in DMSO are transferred to a kinase reaction mixture using sonication (Echo 550) at an initial concentration of 10. Mu.M for the test compounds, a total of 10 concentrations at 4-fold decreasing dilution. After incubation for 15 minutes, 33 P-ATP (illuminance 0.01. Mu. Ci/. Mu.L final) was added to the reaction system to initiate the reaction. Incubating the kinase reaction for 120 minutes at room temperature; the reaction was transferred to P81 ion exchange paper (Whatman # 3698-915). The filter membrane was extensively washed with 0.75% (v/v%) phosphoric acid and the residual radiophosphorylated substrate on the filter paper was measured. Kinase activity data are expressed as the ratio of kinase activity in test wells (containing test compound) to blank wells (containing DMSO only) and were curve fitted by Prism4 software (GraphPad) to give IC 50 values, the experimental results are shown in table 3.
Table 1: information about substrates in vitro assays
Table 2: information about kinase and ATP in vitro assays
Table 3: activity of test Compounds on FGFR1-4 wild-type kinase (IC 50, nM)
| Compounds of formula (I) | FGFR1 | FGFR2 | FGFR3 | FGFR4 |
| TAS-120 | 0.784 | 0.397 | 1.340 | 4.650 |
| Compound A | 0.155 | 0.085 | 0.790 | 0.292 |
Note that: TAS-120 is purchased from Glpbio, catalog number GC191561.
Conclusion: the compound A can obviously inhibit the activity of FGFR1-4 wild type kinase, and the effect is better than that of a reference compound TAS-120.
Example 2: human and mouse plasma stability test
The test method comprises the following steps: thawing frozen blood plasma for 10-20 min, centrifuging at 3220 Xg (centrifugal force) for 5min after the blood plasma is completely thawed, and removing suspended substances and sediments. Plasma pH was determined and the pH was adjusted to the range of 7.40.+ -. 0.10 with 1% (v/v%) phosphoric acid solution or 1M sodium hydroxide solution. 96 Kong Fuyo plates were prepared and named T0 (0 min), T10 (10 min), T30 (30 min), T60 (60 min), T120 (120 min), respectively. To the corresponding incubation plate 198 μl of mouse or human blank plasma was added, and then 2 μl of working solution (DMSO solution) of test compound was added to the corresponding incubation plate (two parallel wells were prepared per sample). All samples were incubated in a 37 ℃ water bath. The final incubation concentration of the test compound was 2. Mu.M and the final organic phase content was 1.0% (v/v%). At the end of each incubation time point, the corresponding incubation plate was removed and 400 μl of acetonitrile precipitated protein was added to each corresponding sample well. After all sample plates were pelleted and shaken well, they were centrifuged at 3220 Xg for 20 minutes. 50. Mu.L of the supernatant was diluted with 100. Mu.L of ultrapure water, and the mixture was analyzed by the LC/MS/MS method.
The experimental results are shown in table 4.
Table 4: plasma stability test results
Conclusion: compound a has better stability in both mouse and human plasma than the reference compound in the table (example 8 (S configuration) in WO2019034076 A1).
Example 3: evaluation of in vitro inhibitory Activity of mutant kinase
The inhibition of each mutant FGFR kinase by test compound A was determined by 33 P-ATp membrane filtration.
Buffer conditions ：20mM Hepes(pH 7.5),10mM MgCl2,1mM EGTA,0.02％Brij35,0.02mg/mL BSA,0.1mM Na3VO4,2mM DTT,1％DMSO.
The test steps are as follows: the substrate (see Table 5) was added to the freshly prepared reaction buffer, and the specific kinase (see Table 6) was added to the substrate solution and gently mixed. Compounds dissolved in DMSO are transferred to a kinase reaction mixture using sonication (Echo 550) at an initial concentration of 10. Mu.M for the test compounds, a total of 10 concentrations at 4-fold decreasing dilution. After incubation for 15 minutes, 33 P-ATP (illuminance 0.01. Mu. Ci/. Mu.L final) was added to the reaction system to initiate the reaction. Kinase reaction was incubated at room temperature for 120 min, the reaction was transferred to P81 ion exchange paper (Whatman # 3698-915) and the filter membrane was extensively washed with 0.75% phosphoric acid; the remaining radio-phosphorylated substrate on the filter paper was measured. Kinase activity data are expressed as the ratio of kinase activity in test wells (containing test compound) to blank wells (containing DMSO only) and were curve fitted by Prism4 software (GraphPad) to give IC 50 values, the experimental results are shown in table 7.
Table 5: information about the substrate
Table 6: information about kinase and ATP
Table 7: activity of test Compounds on FGFR mutant enzymes (IC 5, nM)
| Kinase enzymes | TAS-120 | BGJ-398 | Compound A |
| FGFR1(V561M) | 605 | 1310 | 26.8 |
| FGFR2(E565G) | 1.37 | 7.24 | 0.12 |
| FGFR2(N549H) | 2.36 | 29.8 | 0.23 |
| FGFR2(V564F) | 255 | 6520 | 42.1 |
| FGFR3(K650M) | 1.99 | 27 | 0.17 |
| FGFR3(V555M) | 22.8 | 888 | 24.7 |
| FGFR4(N535K) | 8020 | 10200 | 17.5 |
| FGFR4(V550M) | 93.9 | 3960 | 4.24 |
Note that: BGJ-398 is purchased from Glpbio, catalog number GC10055.
Conclusion: the compound A can obviously inhibit the activity of FGFR1-4 mutant kinase, and the effect is better than that of reference compounds TAS-120 and BGJ-398.
Example 4: evaluation of proliferation inhibitory Activity of human gastric cancer cells, bladder cancer cells and liver cancer cells
The inhibition of proliferation of human gastric cancer cells (SNU-16), FGFR3 high expression and FGFR3-TACC3 fused human bladder cancer cells (RT 112/84) and FGFR4/FGF19 high expression human liver cancer cells (Hep 3B) amplified by the FGFR2 gene by the tested compound A is determined by adopting a CellTiter-Glo TM living cell detection kit. Wherein, the culture medium of SNU-16 was PRMI-1640 medium (Invitrogen, cat# 11875093) supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin solution, and the culture medium of Hep3B cells and RT112/84 cells was EMEM medium (ATCC, cat# 30-2003) supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin solution.
The test steps are as follows: SNU-16, RT112/84 and Hep3B cells, which had reached 80% cell fusion, were digested with pancreatin, counted by centrifugation and resuspended, and each of 100000, 20000 and 70000 cells/mL of SNU-16, RT112/84, hep3B cell suspensions were prepared with medium, 96-well cell culture plates (90. Mu.L/well) were added, and incubated at 37℃in a cell incubator containing 5% CO 2. After 24 hours of cell culture, the reference compound epirubicin (Epirubicin) and test compound A were dissolved in DMSO to give a stock solution at a concentration of 30 mM. Further dilution of the diluted compound stock solution was performed with SNU-16, RT112/84 and Hep3B medium, and the diluted mixture was transferred to the corresponding cell plates, respectively, with a final concentration of the test compound of 30. Mu.M (as initial concentration for IC50 test), 9 concentrations were diluted 5-fold by 5-fold decrease, and 9 concentrations were: 30. Mu.M, 6. Mu.M, 1.2. Mu.M, 0.24. Mu.M, 0.048. Mu.M, 0.0096. Mu.M, 0.0019. Mu.M, 0.0004. Mu.M and 0.00008. Mu.M, were mixed and centrifuged, and incubated at 37℃for 3 days in a cell incubator containing 5% CO 2. The 96-well cell culture plate was removed, cellTiterGlo (CTG, chemiluminescent cell Activity detection kit) reagent (100. Mu.L/well) was added, mixed well and centrifuged, and incubated at room temperature for 10 minutes. Envision multi-label analyzer readings were used. The inhibition rate is calculated according to the original data, and the inhibition rate calculation formula is as follows: inhibition% = (DMSO control-assay wells)/(DMSO control-culture medium control) ×100. Data analysis was performed using XLFit statistics software to calculate IC 50. The experimental results are shown in table 8.
Table 8: inhibition of proliferation of SNU-16, RT112/84 and Hep3B cells by Compound A (IC 50, nM)
| Compounds of formula (I) | SNU-16 | RT112/84 | Hep3B |
| Compound A | 5.0 | 2.3 | 5.1 |
| Epirubicin | 274.6 | 75.9 | 451.9 |
Note that: epirubicin purchased from TOCRIS, cat No. 3260, lot No. 2a7193516.
Conclusion: the compound A has obvious inhibition effect on the proliferation of SNU-16, RT112/84 and Hep3B cells to be tested, and can be used for obviously inhibiting the proliferation of tumor cells with abnormal FGFR expression, and the effect is better than that of a reference compound broad-spectrum anticancer drug Epirubicin.
Example 5: evaluation of human bile duct cancer cell proliferation inhibitory Activity
The inhibition effect of the tested compound A on proliferation of human bile duct cancer cells HuCCT and human intrahepatic bile duct cancer cells RBE, which are highly expressed by FGFR2, is determined by adopting an MTT method. The cell culture medium used was PRMI-1640 medium (Gibco, lot number: 8119264) supplemented with fetal bovine serum at a final concentration of 10%.
The test steps are as follows: cells in the logarithmic growth phase were inoculated in a certain amount into 96-well plates (100. Mu.L/well), 100. Mu.L of a culture solution containing compound A or control TAS-120 having different concentration gradients was added to each well after 24 hours of adherence, 3 compound wells were set for each drug concentration, and corresponding blank wells (medium only) and normal wells (drug concentration 0) were set. After 72 hours of drug action, MTT working solution (5 mg/mL, 20. Mu.L per well) was added, the reaction was carried out at 37℃for 4 hours, the supernatant was removed by shaking the plate, and 150. Mu.L of DMSO (analytically pure) was added; the plate was wiped clean by shaking with a micro-well shaker and the Optical Density (OD) was measured at 550nm with an microplate reader.
The inhibition of cell growth was calculated using the following formula:
Inhibition (%) = (OD value Normal hole -OD value Drug delivery hole )/(OD value Normal hole -OD value Blank hole ) ×100%
Based on the respective concentration inhibition ratios, the drug half inhibition concentration IC 50 was calculated using SPSS 19.0. The experimental results are shown in table 9.
Table 9: inhibition of HuCCT, RBE cell proliferation by Compound A (IC 50, μM)
| Compounds of formula (I) | HuCCT1 | RBE |
| Compound A | 1.451±0.464 | 1.068±0.130 |
| TAS-120 | ＞20 | ＞200 |
Conclusion: compound a has a better inhibitory effect on both HuCCT and RBE cell proliferation tested, while TAS-120 has little inhibitory effect on HuCCT and RBE cell proliferation, with a significant difference.
Example 6: in vivo pharmacodynamics evaluation of human gastric cancer SNU-16 cell subcutaneous xenograft tumor BALB/c nude mouse model
The inhibition effect of the compound A on human gastric cancer is determined by adopting a human gastric cancer SNU-16 xenograft tumor BALB/c nude mouse model amplified by FGFR2 genes.
Cell culture: SNU-16 cells were cultured in vitro in RPMI-1640 medium containing 10% fetal bovine serum and 2mM L-glutamine at 37℃in an incubator containing 5% CO 2. Passaging was performed twice a week with conventional digestion treatments with pancreatin-EDTA. When the cell saturation is 80% -90% and the number reaches the requirement, the cells are collected, counted and tested according to the following steps.
The test steps are as follows: 0.2mL of a cell suspension containing 5X 10 6 SNU-16 cells and a primer (PBS: primer (Matrigel) =1:1 (v/v)) was inoculated subcutaneously into the right back of each mouse. On day 13 post inoculation, when the average tumor volume reached 144mm 3, 6 mice per group were grouped by hierarchical randomization. Reference compound TAS-120 and test compound A were dissolved in an aqueous solution containing 0.5% (w/v) Methylcellulose (MC) and 0.5% (v/v) Tween 80 to form an appropriate solution, and the solution was administered to mice by gavage at a dose of 10mL/kg for 28 consecutive days. Tumor diameters were measured twice weekly with vernier calipers. The calculation formula of the tumor volume is: v=0.5a×b 2, a and b represent the long and short diameters of the tumor, respectively.
The tumor inhibiting effect of the compound is expressed by tumor growth inhibition rate (tumor inhibition rate for short) TGI (%). Calculation of TGI (%): TGI (%) = [ (1- (mean tumor volume at the end of the treatment group administration-mean tumor volume at the beginning of the treatment group administration))/(mean tumor volume at the end of the treatment with solvent control group-mean tumor volume at the beginning of the treatment with solvent control group) ]x100%.
The experimental results are shown in table 10.
Table 10: effect of compound a on tumor volume (mean ± SEM, mm 3, n=6) of SNU-16 xenograft model tumor
Note that: two comparisons were analyzed with T-test, three or more comparisons were analyzed with one-way ANOVA, and data analysis was performed using Prism.
Conclusion: compound a was given once daily (QD) at doses of 10, 20 and 40mg/kg, all had a remarkable tumor-inhibiting effect, and the tumor-inhibiting effect had a dose-dependent trend. The tumor inhibition rates (TGI) were 63%, 86% and 98% respectively after 28 days of administration, and p-values were less than 0.05 compared with the solvent control group. The tumor inhibiting effect of the compound A is better than that of TAS-120 at the same dosage, and the curative effect difference of the compound A and the compound A is obvious at the dosage of 40mg/kg, thus having statistical significance (p is less than 0.05).
Example 7: in vivo pharmacodynamics evaluation of human bladder cancer RT112/84 cell subcutaneous xenograft tumor BALB/c nude mouse model
The inhibition effect of the compound A on human bladder cancer is determined by adopting a BALB/c nude mouse model of human bladder cancer cell RT112/84 xenograft tumor fused with FGFR3 high expression and FGFR3-TACC 3.
Cell culture: RT112/84 cells were grown in vitro in monolayer under conditions of EMEM medium (Gibco, cat# 11140076) containing 10% fetal bovine serum, 1% NEAA (optional amino acids), 2mM L-glutamine in incubator containing 5% CO 2 at 37 ℃. Passaging was performed twice a week with conventional digestion treatments with pancreatin-EDTA. When the cell saturation is 80% -90% and the number reaches the requirement, the cells are collected, counted and tested according to the following steps.
The test steps are as follows: 0.2mL of a cell suspension (PBS: matrigel=1:1 (v/v)) containing 10X 10 6 RT112/84 cells and the base gel was inoculated subcutaneously into the right back of each mouse. When the average tumor volume reached 188mm 3, 8 mice per group were grouped by hierarchical randomization. Control compound TAS-120 and test compound A were dissolved in an aqueous solution containing 0.5% (w/v) MC and 0.5% (v/v) Tween 80 to form appropriate solutions, and the mice were administered by gavage at a dose volume of 10mL/kg for 20 consecutive days. Tumor diameters were measured twice weekly with vernier calipers. The calculation formula of the tumor volume is: v=0.5a×b 2, a and b represent the long and short diameters of the tumor, respectively.
The tumor-inhibiting effect of the compound is expressed as tumor growth inhibition rate TGI (%). Calculation of TGI (%): TGI (%) = [ (1- (mean tumor volume at the end of the treatment group administration-mean tumor volume at the beginning of the treatment group administration))/(mean tumor volume at the end of the treatment with solvent control group-mean tumor volume at the beginning of the treatment with solvent control group) ]x100%.
The experimental results are shown in table 11.
Table 11: effect of compound a on tumor volume (mean ± SEM, mm 3, n=8) of RT112/84 xenograft tumor model
Conclusion: compound a had significant tumor inhibiting effects given once daily (QD) at doses of 5, 10 and 20 mg/kg. For 20 days of administration, tumor inhibition rates (TGI) were 67%, 79% and 83%, respectively, with p values of less than 0.05 compared to the solvent control group. At a dose of 20mg/kg, compound A has comparable tumor inhibiting effect with TAS-120.
Example 8: in vivo pharmacodynamics evaluation of human liver cancer LI-03-0332 subcutaneous xenograft model
The inhibition effect of the compound A on human liver cancer is determined by adopting a subcutaneous transplantation tumor model constructed by nude mice after the LI-03-0332 human liver cancer tissue with high FGFR3 expression is inoculated.
Tumor tissue: the establishment of the model of human liver cancer LI-03-0332 was originally derived from a clinical sample from surgical excision. The collection and use of specimens strictly complies with national, hospital and company-related ethical laws and regulations. The passaging naming rules are: the tumor sample is inoculated in a nude mouse and then is P0 generation, the continuous generation is P1 generation, so that the resuscitated sample is named as FP, and the tumor tissue used in the experiment is FP9 generation.
The test steps are as follows: LI-03-0332 tumor tissue is cut into small blocks of 20-30mm 3 after necrotic tissue is removed, and liver cancer tumor tissue is inoculated subcutaneously on the right back of each mouse after base gum is added, and 149 mice are inoculated altogether. On day 22 post inoculation, when the average tumor volume reached 135mm 3, the animals were grouped by random stratification grouping method based on tumor volume and animal weight, the solvent control group was 6 mice, and the remaining groups were 8 mice each. Control compound TAS-120 and test compound A were dissolved in an aqueous solution containing 0.5% (w/v) MC and 0.5% (v/v) Tween 80 to form an appropriate solution, and the solution was administered to mice by gavage at a dose of 10mL/kg for 21 consecutive days. Tumor diameters were measured twice weekly with vernier calipers. The calculation formula of the tumor volume is: v=0.5a×b 2, a and b represent the long and short diameters of the tumor, respectively.
The tumor-inhibiting effect of the compound is expressed as tumor growth inhibition rate TGI (%). Calculation of TGI (%): TGI (%) = [ (1- (mean tumor volume at the end of the treatment group administration-mean tumor volume at the beginning of the treatment group administration))/(mean tumor volume at the end of the treatment with solvent control group-mean tumor volume at the beginning of the treatment with solvent control group) ]x100%.
The experimental results are shown in table 12.
Table 12: effect of Compound A on LI-03-0332 xenograft tumor model tumor volume (mean.+ -. SEM, mm 3)
Note that: the solvent control group contained 6 animals, the other groups being 8 animals.
Conclusion: compound a had significant tumor inhibiting effects given once daily (QD) at doses of 5, 10 and 20 mg/kg. The tumor inhibition rates (TGI) were 81%, 79% and 87% respectively after 21 days of administration, and p-values were less than 0.0001 compared with the solvent control group. At a dose of 20mg/kg, compound A has comparable tumor inhibiting effect with TAS-120.
Example 9: evaluation of off-target Effect on important kinases
The inhibition of compound a on various non-target kinase activities was analyzed using the eurofins company Enzyme Profiling Services technology platform. Compounds were tested for each Kinase using the Eurofins standard Kinase Profiler TM protocol, which followed the relevant standard protocol. Protein kinase (except ATM (h) and DNA-PK (h)) tests were tested with the amount of radiation, while lipid kinase, ATM (h), ATR/ATRIP (h) and DNA-PK (h) tests were tested withAnd (5) detecting.
The test steps are as follows: taking a proper amount of working solution (100% DMSO is dissolved) which is 50 times that of the test compound A into a test hole (the final concentration of the compound A is 0.1 mu M), and then adding the evenly mixed kinase and substrate mixed solution; adding ATP solution with selected concentration to start reaction; the mixture of kinase and substrate and compound does not require pre-incubation prior to ATP addition.
The experimental results are shown in table 13.
Table 13: off-target effect evaluation result
Conclusion: at a concentration of 0.1 μm, compound a had no significant inhibition of more than 50 kinases tested.
Example 10: safety pharmacological evaluation
The effect of single gastric lavage administration of test compound a on SD rat central nervous system function was assessed using a functional observational combination test (FOB). The male and female rats were divided into 4 groups of 5 animals each, and the vehicle (aqueous solution containing 0.5% (w/v) methylcellulose and 0.2% (w/v) tween 80) or compound a at doses of 0.5, 1.2 and 3mg/kg was orally administered. All animals were dosed at 5mL/kg. The test subjects animals were observed for mortality and weighed. FOB observations were made before the test, 2 hours after the administration, 8 hours after the administration, and 24 hours after the administration, respectively. The observation indicators include motor function, behavior change, coordination function, sensory/motor reflex, and body temperature. As a result, no change was seen in relation to the test article at each observation time point. Under the conditions of this test, no effect of test compound a on the central nervous system of rats was seen.
Using telemetry, the effect of oral gavage administration of test compound a on the cardiovascular parameters of awake beagle dogs was evaluated. The control formulation (vehicle: an aqueous solution containing 0.5% (w/v) methylcellulose and 0.2% (w/v) tween 80), and a dose of 0.3, 0.6 or 2mg/kg of test compound a, were administered orally to male and female dogs. Animals were observed daily for survival. Cage side observations were made 2 times daily on non-dosing days, with one detailed clinical observation before and after each dose. The electrocardiogram, heart rate and blood pressure were continuously recorded for all experimental animals at least 2 hours prior to each administration to about 24 hours after administration. Electrocardiogram waveforms of about 30 seconds in length were printed at 2 time points (at least 30 minutes apart) before each administration and at 6 time points (0.5 hours, 1 hour, 2 hours, 4 hours, 12 hours, and 24 hours post administration) after administration. The results showed that under the present test conditions, no test-related cardiovascular index changes were seen within 24 hours after administration of compound a at doses of 0.3, 0.6 and 2mg/kg per single oral gavage of beagle.
The SD rats were given a single oral gavage of test compound a and their effect on respiratory function was assessed. The male and female rats were divided into 4 groups of 5 animals each, and a control preparation (vehicle: an aqueous solution containing 0.5% (w/v) methylcellulose and 0.2% (w/v) tween 80) or 0.5, 1.2 or 3mg/kg of test compound a was orally administered. All animals were dosed at 5mL/kg. Prior to dosing, about 15 minutes of respiratory data (tidal volume, respiratory rate, ventilation per minute) were collected as a pre-packet respiratory parameter baseline. The time points on the day of administration were before administration, 2 hours after administration, 8 hours after administration, and 24 hours after administration, each of which data was collected once for about 15 minutes. The results showed that 24 hours after a single oral administration, no effect of the test sample on the respiratory rate, tidal volume and minute ventilation of the rats was seen.
The experimental results are shown in table 14.
Table 14: results of safety pharmacological test
Conclusion: compound a had no effect on both the central nervous system and respiratory system of SD rats and on the cardiovascular system of beagle dogs, suggesting that compound a has higher safety.
Example 11: acute toxicity test
1. Toxicity test of single gastric lavage administration of rat
The test method comprises the following steps: the maximum tolerated dose of Compound A was tested by randomly dividing 40 rats into 4 groups of 10, male and female halves, each given a single oral gavage of Compound A and control solvent at a dose of 10, 40 or 400mg/kg, respectively, in an aqueous solution containing 0.5% (w/v) MC and 0.2% (w/v) Tween 80. The dosing volume was 10mL/kg and the observation period was 14 days.
Test results: a slight increase in yellow abnormal feces and total bilirubin was observed only in the 400mg/kg dose group. The other dose groups of male and female animals did not show any significant differences in the death, clinical symptoms, macroscopic lesions, weight changes, feeding, clinical examination (hematology, hemagglutination, serum biochemistry, urinalysis) relative to the solvent control group. Thus, the Maximum Tolerated Dose (MTD) for a single administration under the conditions of this test was 400mg/kg.
2. Toxicity test of canine single gastric lavage drug administration
The test method comprises the following steps: 8 beagle dogs were randomly divided into 4 groups of 2 dogs each, each half of which were administered compound A and control solvent in a single oral gavage at a dose of 15, 50 or 250mg/kg, respectively, and the solvent was an aqueous solution containing 0.5% (w/v) MC and 0.2% (w/v) Tween 80. The administration volume was 5mL/kg. Animals were fasted overnight prior to dosing. The observation period was 14 days. The male and female animals were examined by dissection on day 21.
Test results: single dose gavage administration of 15, 50 or 250mg/kg of compound a to beagle did not produce test-related mortality, clinical symptoms, body weight, food intake, hematology, hemagglutination, serum biochemistry, urine analysis parameters, macroscopic lesions and histopathological adverse reactions. Therefore, the Maximum Tolerated Dose (MTD) of the male and female beagle dogs under the test conditions is considered to be 250mg/kg.
Conclusion: the compound A has higher tolerance dose in a toxicity test of single gastric lavage administration and good safety.
Various aspects of the present invention have been illustrated by the above embodiments. It is apparent that the above embodiments are given for the purpose of illustration only and are not intended to limit the scope of the present invention in any way. Other variations and modifications of the above teachings will be apparent to those of ordinary skill in the art, and it is to be understood that these variations are not intended to be limiting. It is not necessary here nor is it exhaustive of all embodiments. While still being within the scope of the invention, obvious variations or modifications may be made thereto.
Claims (17)
1. Use of an FGFR inhibitor compound a or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of FGFR-associated tumors, wherein the compound a has the structure:
Wherein the FGFR-associated tumor is any one or any combination of gastric cancer, liver cancer, urothelial cancer and cholangiocarcinoma.
2. The use of claim 1, wherein the liver cancer is any one of hepatocellular carcinoma, intrahepatic cholangiocarcinoma, mixed liver cancer, or any combination thereof; the urothelial cancer is bladder cancer; the bile duct cancer is any one or any combination of intrahepatic bile duct cancer, porta hepatis bile duct cancer and distal bile duct cancer.
3. The use of claim 2, wherein the cholangiocarcinoma is intrahepatic cholangiocarcinoma.
4. The use of claim 2, wherein the bladder cancer is a bladder cancer with high FGFR3 expression or FGFR3-TACC3 fusion.
5. The use of claim 1, wherein the gastric cancer is FGFR2 gene-amplified gastric cancer, the liver cancer is FGFR4/FGF 19-high expression liver cancer or FGFR 3-high expression liver cancer, and the cholangiocarcinoma is FGFR 2-high expression cholangiocarcinoma.
6. The use according to any one of claims 1-5, wherein said compound a or a pharmaceutically acceptable salt thereof is the sole active ingredient in the medicament, or is used in combination with one or more other targeted or chemotherapeutic drugs.
7. The use according to any one of claims 1-5, wherein the medicament is formulated into a clinically acceptable formulation.
8. The use according to any one of claims 1-5, wherein the medicament is formulated as an oral formulation, an injectable formulation or an external formulation.
9. The use according to any one of claims 1-5, wherein compound a or a pharmaceutically acceptable salt thereof is administered in a daily dosing range from 0.02mg/kg to 50 mg/kg.
10. The use according to any one of claims 1-5, wherein compound a or a pharmaceutically acceptable salt thereof is administered in a daily dosing range from 0.03mg/kg to 20 mg/kg.
11. The use according to any one of claims 1-5, wherein the medicament contains a therapeutically effective amount of compound a or a pharmaceutically acceptable salt thereof.
12. The use of claim 11, wherein the therapeutically effective amount is 0.5-100mg.
13. The use of claim 12, wherein the therapeutically effective amount is 0.5-50mg.
14. The use of claim 12, wherein the therapeutically effective amount is 0.5-30mg.
15. The use of any one of claims 1-5, wherein compound a or a pharmaceutically acceptable salt thereof is administered in a single dose or in divided doses.
16. The use of any one of claims 1-5, wherein the medicament is administered orally, by injection, topically or in vitro.
17. The use according to any one of claims 1-5, wherein the medicament is administered by oral administration or injection.
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