CN114641293A - Application of FGFR inhibitor - Google Patents
Application of FGFR inhibitor Download PDFInfo
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- CN114641293A CN114641293A CN202080076195.1A CN202080076195A CN114641293A CN 114641293 A CN114641293 A CN 114641293A CN 202080076195 A CN202080076195 A CN 202080076195A CN 114641293 A CN114641293 A CN 114641293A
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- fgfr
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Abstract
Use of an FGFR inhibitor is provided. More specifically, an FGFR inhibitor or a pharmaceutically acceptable salt thereof for treating FGFR-related tumors, a pharmaceutical composition comprising the same, a method for treating FGFR-related tumors using a medicament containing the same, and use thereof in preparing a medicament for treating FGFR-related tumors. In vitro and in vivo test results show that the compound A has the activity of inhibiting digestive or urinary system tumors 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.
Description
Cross Reference to Related Applications
This application claims priority to chinese patent application No. 201911086889.9 filed on 8/11/2019 and chinese patent application No. 202010321669.6 filed on 22/4/2020, both of which are hereby incorporated by reference in their entirety.
The invention belongs to the field of medicine. More specifically, the invention relates to an FGFR inhibitor or a pharmaceutically acceptable salt thereof for treating FGFR-related tumors, a pharmaceutical composition comprising the same, a method for treating FGFR-related tumors by using a medicament containing the same and application thereof in preparing a medicament for treating FGFR-related tumors.
Fibroblast Growth Factor Receptors (FGFR) are receptors for Fibroblast Growth Factor (FGF) signaling, and a family thereof is composed 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 show that FGF signaling pathway abnormalities (high expression, gene amplification, gene mutation, chromosome recombination, etc.) are directly associated with many pathological processes such as tumor cell proliferation, migration, invasion, and angiogenesis, and FGFR shows 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, and the like. For example, FGFR2 fusion mutations were found to occur in about 10-20% of intrahepatic cholangiocarcinoma patients; the change of the FGFR3 gene has stronger correlation with low-grade pathological and low-grade clinical cancers in bladder cancer, and more than 70 percent of low-grade pathological non-invasive urothelial papillomas contain FGFR3 mutation; and the high expression of FGFR1, FGFR2 and FGFR3 is found in gastric cancer tissues and gastric cancer cells. Therefore, FGFR becomes an important therapeutic target and attracts extensive research and development interest.
Depending on the mechanism of action, inhibitors targeting the kinase domain within the FGFR membrane can be classified into ATP competitive inhibitors, non-ATP competitive reversible inhibitors and irreversible inhibitors, wherein the inhibitory activity of the non-ATP competitive reversible inhibitors and irreversible inhibitors on kinases is not affected by high ATP concentrations in cells and in vivo. In recent years, some FGFR-targeted drugs for treating the above tumor diseases have entered clinical trials, and Balversa (Erdafitinib) becomes the first worldwide FGFR reversible inhibitor targeting drug approved by FDA for metastatic urothelial cancer. In addition, other FGFR1-4 inhibitors (e.g., BGJ-398, Debio-1347, TAS-120, etc.) are in different clinical stage trials for solid tumors such as urothelial cell carcinoma and liver cancer. The structural formula of the medicine is as follows:
however, researches show that the reversible inhibitor of pan FGFR (pan-FGFR), such as BGJ-398, is difficult to avoid generating drug resistance after being used for 4-6 months, so that the curative effect is reduced, and the irreversible inhibitor, such as TAS-120, is still effective for patients after being resistant to BGJ-398, thereby showing the unique advantages of the irreversible inhibitor. However, no FGFR1-4 irreversible inhibitor has been approved for marketing at home and abroad so far.
Primary liver cancer (liver cancer for short) is a common malignant tumor, is the cause of cancer death of the 4 th cause worldwide, and poses serious threat to human life health. Liver cancer mainly includes hepatocellular carcinoma (HCC), Intrahepatic Cholangiocellular Carcinoma (ICC), and mixed hepatocellular carcinoma (c-CC). Liver cancer has no obvious clinical symptoms in early stage, is found to be in middle and late stages frequently, and has the advantages of high malignancy degree, high recurrence rate, poor treatment effect and poor prognosis. The clinical treatment means for liver cancer mainly include surgical treatment, Transcatheter Arterial Chemoembolization (TACE), radiotherapy and chemotherapy. However, the residual liver tissue of post-operative patients still presents a risk of cancer, with a 5-year risk of recurrence of more than 70%. Sorafenib (Sorafenib) is the only currently approved molecular targeted drug for treating advanced liver cancer, but it is still poorly effective in liver cancer patients with liver function Child-Pugh graded as grade B.
Urothelial cancer (UCC) is a common malignant tumor worldwide and is one of the most common clinical malignant tumors in urology surgery in China, and 90-95% of urothelial cancer is bladder cancer. The initial diagnosis of urothelial cell carcinoma is mostly non-muscle layer infiltrative, but the urothelial cell carcinoma has high recurrence rate; and with the increase of the number of relapses, the malignancy of the tumor is improved and transformed into a muscle-layer-infiltrating tumor. Patients with metastatic urothelial cancer with FGFR gene changes have poor prognosis and low response rate to treatment, and the patients have far-unmet significant clinical requirements. For decades, the standard of treatment for urothelial cancer has been Cisplatin (cissplatin) -based chemotherapy regimens. The second-line chemotherapeutic drugs Vinflunine (Vinflunine) or taxanes (taxanes) have slightly improved efficacy, with historical Objective Remission Rates (ORR) of only about 10% and an overall median survival (OS) of 7-9 months. Advanced or metastatic urothelial cancer also has an overall response rate of only 15% to 20% to the recently approved PD-1/PD-L1 checkpoint inhibitor, with a median OS of about 10 months, and thus many patients do not benefit.
Gastric cancer (gastric cancer) is also one of the common malignant tumors in the world, has relatively poor prognosis and seriously threatens human health. Due to the lack of a mature early screening system, atypical and low-rate detection of early gastric cancer symptoms, most patients are diagnosed with advanced stages. The current therapeutic measures for gastric cancer mainly include surgical treatment, systemic application of chemical drugs, radiotherapy and molecular targeted drug therapy. The targeted therapy is the drug therapy aiming at the specific target of the tumor, but because of strong heterogeneity of the gastric cancer and the like, the clinical research on the targeted therapy of the gastric cancer is less successful and has more failures.
Cholangiocarcinoma (CCA) is an epithelial malignancy with distinct cholangiocellular differentiation characteristics, with an increased incidence of nearly 20% over the past 10 years, accounting for approximately 3% of digestive tract tumors and 10-15% of hepatobiliary malignancies. Biliary tract cancers can be classified, depending on the anatomical location, as intrahepatic and extrahepatic cholangiocarcinoma (eCCA), which is further classified as supraportal cholangiocarcinoma (pCCA) and distal cholangiocarcinoma (dCCA). Radical surgery is the only cure, but there is no characteristic clinical manifestation in the early stage of the disease, about 2/3 patients lose the chance of surgery at the time of initial diagnosis, and 5-year survival rate is about 10%. Even after surgical resection, the 1-year recurrence rate of cholangiocarcinoma is still as high as 50%. For unresectable local progression stage metastatic biliary tumors (including intrahepatic and extrahepatic bile duct cancer, gallbladder cancer (ampulla ampullate), etc.), the standard first-line chemotherapy regimen (gemcitabine in combination with cisplatin) only resulted in median survival of 11.7 months with very poor prognosis. However, the FGFR inhibitor has shown a prospect in the clinical test of the bile duct cancer, for example, the FGFR inhibitor BGJ-398 obtains excellent phase II test results in advanced bile duct cancer with FGFR gene fusion, mutation and amplification, and the objective remission rate and the disease control rate reach 18.8% and 83.3% in FGFR gene fusion patients.
Intrahepatic cholangiocarcinoma refers to malignant tumor of biliary duct epithelium at two or more levels in liver, also called intrahepatic cholangiocarcinoma, belongs to one of primary liver cancer (accounting for 10% -15%), and can also belong to one of bile duct cancer (accounting for about 10%) according to the occurrence part. The intrahepatic bile duct cancer has high malignancy degree, extremely strong invasion and lymph node metastasis characteristics, difficult early diagnosis and poor patient prognosis, the overall survival rate of 5 years is lower than 10 percent, and the median survival time after surgical resection is 36 months. The only current method for curing intrahepatic bile duct cancer is early detection and surgical resection, but the recurrence rate after resection is high. Patients with locally advanced unresectable and recurrent metastases are even deficient in effective measures that significantly improve prognosis. Intrahepatic bile duct cancer is insensitive to traditional chemotherapy, radiotherapy and recent tumor immunotherapy, and no standard treatment method is available for bile duct cancer patients who fail to receive first-line gemcitabine chemotherapy. The literature reports that patients receiving second-line chemotherapy with various regimens of 5-fluorouracil (5-FU) and irinotecan, 5-FU and oxaliplatin, 5-FU and cisplatin, 5-FU or capecitabine and sunitinib have median progression-free survival (PFS) and Overall Survival (OS) of 3.2 and 6.7 months, respectively, with no significant difference in PFS or OS between the regimens. The molecular mechanism research of intrahepatic bile duct cancer has been reported more. A comprehensive genome analysis of 260 cholangiocarcinoma patients by Nakamura et al revealed that 40% of cases exhibited an alteration in the FGFR gene, with FGFR2 exhibiting high expression in intrahepatic cholangiocarcinoma. It is also found by using a second-generation sequencing technology that 13% -50% of patients with intrahepatic bile duct cancer carry FGFR2 gene fusion, wherein 13.6% of patients containing FGFR2-BICC1 and FGFR2-AHCYL1 gene fusion. These findings provide new opportunities for the treatment of intrahepatic bile duct cancer.
Currently, several FGFR inhibitors are currently in different stages of clinical study on bile duct cancer, such as BGJ-398 (reversible selective inhibitor), ARQ087(ATP competitive inhibitor), TAS-120 (irreversible pan FGFR inhibitor), etc., and the FGFR inhibitor used in bile duct cancer was first reported to be BGJ-398. Studies report that 3 patients with FGFR2 fusion positive intrahepatic bile duct cancer treated with BGJ-398 develop clinically acquired FGFR inhibitor resistance, and further studies found polyclonal secondary mutations in the kinase domain of FGFR2, which included the FGFR2V564F gene mutation in all of the 3 patients. TAS-120 is a highly selective irreversible pan FGFR inhibitor. The research shows that the TAS-120 has clinical curative effect on BGJ-398 resistant intrahepatic bile duct cancer patients, and can inhibit secondary mutation of various FGFR 2. However, no document discloses data on the cellular level inhibitory activity of TAS-120. At present, no targeted medicine for treating intrahepatic bile duct cancer is approved to be on the market.
WO2019034076a1 discloses FGFR inhibitors and their medical use, including compound a (example 2). The patent application discloses the evaluation result of the in vitro inhibitory activity of the compound A on FGFR wild type kinase, the evaluation result of the in vitro inhibitory activity of mutant type kinase and the evaluation result of pharmacokinetics in mice, but does not disclose that the compound A can be specifically used for treating diseases.
Disclosure of Invention
[ OBJECTS OF THE INVENTION ]
The invention aims to provide application of a Fibroblast Growth Factor Receptor (FGFR) inhibitor compound A or a pharmaceutically acceptable salt thereof in preparing a medicament for treating FGFR-related tumors.
It is another object of the present invention to provide an FGFR inhibitor compound a or a pharmaceutically acceptable salt thereof for use in the treatment of FGFR-associated tumors.
It is another object of the invention to provide a method of treating a FGFR-associated tumor comprising administering to a subject or patient a medicament containing a therapeutically effective amount of an 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 the treatment of FGFR-associated tumors comprising an FGFR inhibitor compound a or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier.
[ technical solution ] of the present invention
The invention aims to provide a small molecular compound with excellent FGFR1-4 wild type and mutant kinase inhibition activity, a pharmaceutical composition, application and a 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 anti-FGFR related tumor (especially digestive or urinary system tumor) activity, and a pharmaceutical composition, use and a therapeutic method thereof.
The invention provides a small molecular compound with excellent FGFR1-4 wild type and mutant kinase inhibition activity, excellent in vitro/in vivo anti-FGFR related tumor (especially digestive or urinary system tumor) activity and good safety, and a pharmaceutical composition, application and a treatment method thereof.
Still another technical problem to be solved by the present invention is to provide a small molecule compound, a pharmaceutical composition, a use and a therapeutic method thereof, which have excellent FGFR1-4 wild type and mutant kinase inhibitory activity, excellent in vitro/in vivo anti-FGFR related tumor (especially digestive or urinary system tumor) activity, and excellent plasma stability and safety.
In order to solve the above technical problems, the inventors of the present application have further tested on the basis of WO2019034076a1 in the prior art, and as a result, found that compound a has good inhibitory activity on both wild-type FGFR1-4 and mutant FGFR1-4, can significantly inhibit the proliferation of tumor cells of the digestive or urinary system and xenograft tumor models related to the abnormal expression of FGFR1-4, and has high plasma stability and safety, thereby suggesting that compound a can be used for the development of a drug for treating digestive or urinary system tumor diseases related to FGFR 1-4. The results of these studies led to the completion of the technical solution of the present invention.
In particular, in a first aspect of the 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 an FGFR-associated tumor, wherein said compound a has the following structure:
in one embodiment, the FGFR-associated tumor is one or more of a digestive or urological tumor.
In one embodiment, the FGFR-associated tumor is any one of gastric cancer, liver cancer, urothelial cancer, biliary cancer, or any combination thereof.
In one embodiment, the FGFR-associated tumor is gastric cancer. In a preferred embodiment, the gastric cancer is a gastric cancer with an amplified FGFR2 gene.
In one embodiment, the FGFR-associated tumor is liver cancer. In a preferred embodiment, the liver cancer is a liver cancer highly expressing FGFR4/FGF 19. In a preferred embodiment, the liver cancer is a liver cancer with high expression of FGFR 3. In a preferred embodiment, the liver cancer is any one of hepatocellular carcinoma, intrahepatic cholangiocellular carcinoma, mixed liver cancer, or any combination thereof.
In one embodiment, the FGFR-associated tumor is a urothelial cancer. In a preferred embodiment, the urothelial cancer is bladder cancer. In a preferred embodiment, the bladder cancer is a bladder cancer with high expression of FGFR3 and fusion of FGFR3-TACC 3.
In one embodiment, the FGFR-associated tumor is cholangiocarcinoma. In a preferred embodiment, the cholangiocarcinoma is a cholangiocarcinoma with high FGFR2 expression. In a preferred embodiment, the cholangiocarcinoma is any one of intrahepatic cholangiocarcinoma, hepatoportal cholangiocarcinoma, distal cholangiocarcinoma, or any combination thereof. In a more preferred embodiment, the cholangiocarcinoma is an 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 drugs.
In one embodiment, the medicament is formulated for clinical acceptance. In a preferred embodiment, the formulation is an oral formulation, an injectable formulation or a topical formulation.
In one embodiment, the Compound A or a pharmaceutically acceptable salt thereof is administered at a daily dosage range of 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 of 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 at a daily dosage range of 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 at a daily dosage range of 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 0.001-1000 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.
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 medicament 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 an FGFR-associated tumor, wherein the compound a has the following structure:
in one embodiment, the FGFR-associated tumor is one or more of a digestive or urological tumor.
In one embodiment, the FGFR-associated tumor is any one of gastric cancer, liver cancer, urothelial cancer, biliary cancer, or any combination thereof.
In one embodiment, the FGFR-associated tumor is gastric cancer. In a preferred embodiment, the gastric cancer is a gastric cancer with an amplified FGFR2 gene.
In one embodiment, the FGFR-associated tumor is liver cancer. In a preferred embodiment, the liver cancer is a liver cancer highly expressing FGFR4/FGF 19. 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 cholangiocellular carcinoma, mixed liver cancer, or any combination thereof.
In one embodiment, the FGFR-associated tumor is a urothelial cancer. In a preferred embodiment, the urothelial cancer is bladder cancer. In a preferred embodiment, the bladder cancer is a bladder cancer with high FGFR3 expression and FGFR3-TACC3 fusion.
In one embodiment, the FGFR-associated tumor is cholangiocarcinoma. In a preferred embodiment, the cholangiocarcinoma is a cholangiocarcinoma with high FGFR2 expression. In a preferred embodiment, the cholangiocarcinoma is any one of intrahepatic cholangiocarcinoma, hepatoportal cholangiocarcinoma, distal cholangiocarcinoma, 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 drugs.
In one embodiment, the compound a or a pharmaceutically acceptable salt thereof is formulated for clinical acceptance. 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 at a daily dosage range of 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 of 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 at a daily dosage range of 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 at a daily dosage range of 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 0.001-1000 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.
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 containing a therapeutically effective amount of an FGFR inhibitor compound a, or a pharmaceutically acceptable salt thereof, wherein the compound a has the structure:
in one embodiment, the FGFR-associated tumor is one or more of a digestive or urological tumor.
In one embodiment, the FGFR-associated tumor is any one of gastric cancer, liver cancer, urothelial cancer, biliary cancer, or any combination thereof.
In one embodiment, the FGFR-associated tumor is gastric cancer. In a preferred embodiment, the gastric cancer is a gastric cancer with an amplified FGFR2 gene.
In one embodiment, the FGFR-associated tumor is liver cancer. In a preferred embodiment, the liver cancer is a liver cancer highly expressing FGFR4/FGF 19. 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 cholangiocellular carcinoma, mixed liver cancer, or any combination thereof.
In one embodiment, the FGFR-associated tumor is a urothelial cancer. In a preferred embodiment, the urothelial cancer is bladder cancer. In a preferred embodiment, the bladder cancer is a bladder cancer with high FGFR3 expression and FGFR3-TACC3 fusion.
In one embodiment, the FGFR-associated tumor is cholangiocarcinoma. In a preferred embodiment, the cholangiocarcinoma is a cholangiocarcinoma with high FGFR2 expression. In a preferred embodiment, the cholangiocarcinoma is any one of intrahepatic cholangiocarcinoma, hepatoportal cholangiocarcinoma, distal cholangiocarcinoma, 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 for clinical acceptance. 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 at a daily dosage range of 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 of 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 at a daily dosage range of 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 at a daily dosage range of from about 0.03mg/kg to about 20 mg/kg.
In one embodiment, 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.
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 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 following structure:
in one embodiment, the FGFR-associated tumor is one or more of a digestive or urological tumor.
In one embodiment, the FGFR-associated tumor is any one of gastric cancer, liver cancer, urothelial cancer, biliary cancer, or any combination thereof.
In one embodiment, the FGFR-associated tumor is gastric cancer. In a preferred embodiment, the gastric cancer is a gastric cancer with an amplified FGFR2 gene.
In one embodiment, the FGFR-associated tumor is liver cancer. In a preferred embodiment, the liver cancer is a liver cancer highly expressing FGFR4/FGF 19. 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 cholangiocellular carcinoma, mixed liver cancer, or any combination thereof.
In one embodiment, the FGFR-associated tumor is a urothelial cancer. In a preferred embodiment, the urothelial cancer is bladder cancer. In a preferred embodiment, the bladder cancer is a bladder cancer with high FGFR3 expression and FGFR3-TACC3 fusion.
In one embodiment, the FGFR-associated tumor is cholangiocarcinoma. In a preferred embodiment, the cholangiocarcinoma is a cholangiocarcinoma with high FGFR2 expression. In a preferred embodiment, the cholangiocarcinoma is any one of intrahepatic cholangiocarcinoma, hepatoportal cholangiocarcinoma, distal cholangiocarcinoma, 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 drugs as an active ingredient.
In one embodiment, the pharmaceutical composition is formulated for clinical acceptance. 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 at a daily dosage range of 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 at a daily dosage range of 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 at a daily dosage range of 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 at a daily dosage range of 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 0.001-1000 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.
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 various features of the above embodiments of the invention may be combined with each other to form one or more new solutions, which also fall within the scope of the invention, as long as such new solutions are technically feasible.
[ advantageous effects of the invention ]
In order to prove that the compound A is an FGFR1-4 inhibitor which is effective on FGFR-related tumors, particularly digestive or urinary system tumors, the invention evaluates the in vitro kinase inhibition activity of the compound A on FGFR1-4 wild type and mutant type and the proliferation inhibition activity of exemplary digestive or urinary system tumors (including gastric cancer, liver cancer, bladder cancer and bile duct cancer) models related to FGFR, and further evaluates the inhibition effect of the compound A on the tumor growth aiming at a plurality of tumor xenograft models.
In vitro kinase activity test and cell test results show that the compound A has good in vitro kinase inhibition activity on both wild type and mutant type of FGFR 1-4; the compound has good inhibition effect on the proliferation of human gastric cancer cells (SNU-16) with FGFR2 gene amplification, human bladder cancer cells (RT112/84) with FGFR3 high expression and FGFR3-TACC3 fusion, human liver cancer cells (Hep3B) with FGFR4/FGF19 high expression, human bile duct cancer cells HuCCT1 with FGFR2 high expression and human intrahepatic bile duct cancer cells RBE; has obvious inhibiting effect on a human stomach cancer SNU-16 cell subcutaneous xenograft tumor model, a human bladder cancer RT112/84 cell subcutaneous xenograft tumor model and a human liver cancer LI-03-0332 subcutaneous xenograft model.
In addition, in order to examine the drug-forming properties of compound a, the present inventors measured the plasma stability of compound a in human and mouse plasma stability tests and compared it with a reference compound of close structure (example 8(S configuration) in WO2019034076a 1). 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 bonding to a target protein, relative to reversible inhibitors, which is a fundamental reason why irreversible inhibitors exhibit high biological activity. However, if off-target, this affinity enhancement of irreversible inhibitors would also occur at off-target sites, and thus would also lead to enhanced toxic side effects [ see populus et al, small molecule covalent inhibitor research advances, pharmaceutics, 2014, 49 (2): 158-165]. Due to the worry that irreversible inhibitors can bring larger toxic and side effects, the invention detects the off-target effect of the compound A on a plurality of important non-target kinases, and the result shows that the off-target effect of the compound A is lower.
Still further, in order to evaluate the safety of compound a in vivo, the present invention conducted a safe pharmacological test and an acute toxicity test for dogs and mice. The result shows that the compound A has no obvious influence on each detection index and has good safety.
In conclusion, the inventor of the application finds that the compound A has the activity of selectively inhibiting FGFR1-4, has good inhibitory activity on both wild type FGFR1-4 and mutant FGFR1-4, can obviously inhibit the proliferation of digestive or urinary system tumor cells and a xenograft tumor model related to the abnormal expression of FGFR1-4, and has higher plasma stability and safety. Therefore, the compound A has the activity of inhibiting digestive or urinary system tumors 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 ]
As used herein, the following terms and phrases are intended to have the following meanings, unless otherwise indicated. A particular term or phrase, unless specifically defined, should not be considered as indefinite or unclear, but rather construed according to ordinary meaning.
"Compound A" refers to a compound having the structure:
the synthesis can be found in example 2 of WO2019034076A 1.
"pharmaceutically acceptable salt" refers to the conventional non-toxic salts formed by reacting compound a of the present invention with an inorganic acid, an organic acid, an inorganic base, or an organic base. The salts are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. 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 a 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 carriers are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. "FGFR" refers to fibroblast growth factor receptor, a receptor for fibroblast growth factor signaling, which is a family 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.
By "FGFR-associated tumor" is meant a tumor whose development or progression is closely associated with 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, bile duct cancer (e.g., intrahepatic bile duct cancer).
The "targeted drug" refers to a targeted drug for treating tumor-related diseases in clinical use, which is endowed with targeting ability, and can target active ingredients or carriers thereof to a specific target lesion site, and accumulate or release the active ingredients at the site to form a relatively high concentration, thereby improving the curative effect, suppressing toxic and side effects, and reducing the damage to normal tissues and cells.
The chemotherapy medicine is a medicine which can act on different links of tumor cell growth and reproduction and inhibit or kill tumor cells and is clinically used for treating tumor-related diseases, and is one of the main means for treating tumors at present.
By "clinically acceptable formulation" is meant a formulation suitable for use in contact with the tissues of human beings and animals 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. The clinically acceptable preparation comprises oral preparations, injection preparations, external preparations and the like.
According to the present invention, the administration dose and dose frequency of the 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 taking into account factors such as the nature and severity of the disease to be treated, the age, general condition and body weight of the patient, and the particular compound administered, its pharmacokinetic properties, and the route of administration. Suitable daily dosages for said compound a or a pharmaceutically acceptable salt thereof range from about 0.001mg/kg to about 1000 mg/kg; preferably, from about 0.01mg/kg to about 100 mg/kg; further preferably, from about 0.02mg/kg to about 50 mg/kg; even more preferably, from about 0.03mg/kg to about 20mg/kg (wherein "kg" refers to the body weight of the subject (i.e., subject or patient) to which it is administered). Preferably, the daily dose of compound a or a pharmaceutically acceptable salt thereof is 0.001mg to 1000mg, and further preferably, the daily dose of compound a or a pharmaceutically acceptable salt thereof is 0.01mg to 100 mg; still more preferably, the daily dose of compound a or a pharmaceutically acceptable salt thereof is 0.1-50 mg; still more preferably, the daily dose of compound a or a pharmaceutically acceptable salt thereof is 0.5-30 mg; still more preferably, the compound a or a pharmaceutically acceptable salt thereof is administered at a daily dose of 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 single or divided doses.
According to the present invention, said compound a or a pharmaceutically acceptable salt thereof is comprised in said 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 based on compound a.
According to the present invention, the subject or patient suffering from an FGFR-associated tumor can be a human and a non-human mammal such as a mouse, rat, guinea pig, cat, dog, cow, horse, sheep, pig, monkey, 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 in the preparation of a medicament for treating FGFR-related tumors.
2. The use according to claim 1, wherein said tumor comprises gastric cancer, liver cancer, urothelial cancer.
3. The use according to scheme 2, wherein the liver cancer is hepatocellular carcinoma, intrahepatic cholangiocellular carcinoma, or mixed liver cancer.
4. The use according to claim 2, wherein the urothelial cancer is bladder cancer.
5. The use according to any 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 of the claims 1 to 4, characterized in that the medicament is prepared into clinically acceptable formulations, preferably oral formulations, injectable formulations, topical formulations.
7. The use according to any of claims 1 to 4, wherein the inhibitor is administered in a daily dose ranging from about 0.001mg/kg to about 1000 mg/kg; preferably from about 0.01mg/kg to about 100 mg/kg; administration can be single dose or divided dose.
8. The use according to any of the claims 1 to 4, characterized in that the medicament contains a therapeutically effective amount of inhibitor, preferably 0.001-1000 mg; administration can be single dose or divided dose.
Further, the present invention also relates to the following embodiments:
1. use of an FGFR inhibitor compound A or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of an FGFR-related tumor.
2. Use according to protocol 1, characterized in that the tumor is cholangiocarcinoma.
3. Use according to protocol 2, wherein the cholangiocarcinoma comprises intrahepatic cholangiocarcinoma, hepatoportal cholangiocarcinoma and distal cholangiocarcinoma; preferably intrahepatic bile duct cancer.
4. The use according to scheme 1 or 2, wherein the medicament further comprises one or more other targeted drugs, chemotherapeutic drugs.
5. The use according to scheme 1 or 2, wherein the medicament is prepared into clinically acceptable preparations, preferably oral preparations, injection preparations and external preparations.
6. The use according to claim 1 or 2, wherein the medicament comprises a therapeutically effective amount of compound a or a pharmaceutically acceptable salt thereof, preferably a therapeutically effective dose of 0.001mg to 1000mg, more preferably 0.01mg to 100mg, even more preferably 0.1mg to 50mg, even more preferably 0.5mg to 30 mg; administration can be single dose or divided dose.
7. A method of treating a FGFR-associated neoplastic disease, comprising administering to a subject or patient a medicament containing a therapeutically effective dose of 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 cholangiocarcinoma comprises intrahepatic cholangiocarcinoma, hepatoportal cholangiocarcinoma, and distal cholangiocarcinoma; preferably intrahepatic bile duct cancer.
10. The method according to any one of claims 7 to 9, wherein the administration is oral, injectable, topical or in vitro, preferably oral or injectable.
For a further understanding of the present invention, specific embodiments thereof are described in detail below with reference to the examples. It is to be understood that such description is merely for purposes of further illustrating the features and advantages of the invention, and is not to be construed as limiting the aspects of the invention in any way.
Example 1: evaluation of in vitro inhibitory Activity of FGFR1-4 wild type kinase
By using33And (3) testing the inhibition effect of the tested compound A on various wild FGFR kinases by a P-ATP membrane filtration method experiment.
Buffer conditions: 20mM 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid (Hepes) (pH 7.5), 10mM MgCl21mM EGTA, 0.02% (v/v%) Brij35 (Brij35), 0.02mg/mL BSA, 0.1mM Na3VO 4，2mM DTT，1％(v/v％)DMSO。
The test steps are as follows: the test compound was dissolved in DMSO at room temperature to prepare a 10mM solution 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, gently mixed. Compounds dissolved in DMSO were transferred to a kinase reaction mixture using sonication (Echo550) at an initial concentration of 10. mu.M, with 4-fold decreasing dilutions for a total of 10 concentrations of test compound. After incubation for 15 minutes, will33P-ATP (illumination 0.01. mu. Ci/. mu.L final) was added to the reaction system to start the reaction. Incubating the kinase reaction for 120 minutes at room temperature; the reaction was transferred onto P81 ion exchange paper (Whatman # 3698-915). The filtration 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 IC was obtained by curve fitting with Prism4 software (GraphPad)50The values and experimental results are shown in table 3.
Table 1: information relating to substrates in vitro assays
Table 2: information relating to kinases and ATP in vitro assays
Table 3: activity of test Compounds on FGFR1-4 wild-type kinase (IC)50，nM)
| Compound (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: TAS-120 was purchased from Glpbio, catalog number GC 191561.
And (4) 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 the frozen plasma for 10-20 minutes, and after the plasma is completely thawed, centrifuging the plasma in a centrifuge for 5 minutes at 3220 Xg (centrifugal force), and removing suspended matters and precipitates existing in the plasma. Plasma pH was measured and adjusted to a pH range of 7.40. + -. 0.10 using 1% (v/v%) phosphoric acid solution or 1M sodium hydroxide solution. 96-well plates were prepared and designated T0(0min), T10(10min), T30(30min), T60(60min) and T120(120min), respectively. To the corresponding incubation plates, 198 μ L of mouse or human blank plasma was added, and then 2 μ L of working solution of the test compound (DMSO solution) was added to the corresponding incubation plates (two parallel wells were prepared for each sample). All samples were incubated in a 37 ℃ water bath. The final incubation concentration of the test compound was 2 μ 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 μ L of acetonitrile was added to each corresponding sample well to precipitate the protein. After all sample plates were mounted in a membrane and shaken well, they were centrifuged at 3220 Xg for 20 minutes. Taking 50 mu L of supernatant, adding 100 mu L of ultrapure water for dilution, mixing uniformly, and analyzing by an LC/MS/MS method.
The results of the experiment are shown in table 4.
Table 4: results of plasma stability test
And (4) conclusion: compared to the reference compound in the table (example 8(S configuration) in WO2019034076a 1), compound a has better stability in both mouse and human plasma.
Example 3: evaluation of in vitro inhibitory Activity of mutant kinase
By using33P-ATP Membrane filtrationAnd (3) a method experiment for measuring the inhibition effect of the test compound A on each mutant FGFR kinase.
Buffer conditions: 20mM Hepes (pH 7.5), 10mM MgCl2，1mM EGTA，0.02％Brij35，0.02mg/mL BSA，0.1mM Na 3VO 4，2mM DTT，1％DMSO。
The test steps are as follows: the substrate was added to the freshly prepared reaction buffer (see table 5) and the specific kinase (see table 6) was added to the substrate solution, gently mixed. Compounds dissolved in DMSO were transferred to a kinase reaction mixture using sonication (Echo550) at an initial concentration of 10. mu.M, with 4-fold decreasing dilutions for a total of 10 concentrations of test compound. After 15 minutes of incubation, will33P-ATP (illumination 0.01. mu. Ci/. mu.L final) was added to the reaction system to start the reaction. The kinase reaction was incubated at room temperature for 120min, 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 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 IC was obtained by curve fitting with Prism4 software (GraphPad)50The values and experimental results are shown in table 7.
Table 5: information relating to a substrate
Table 6: information relating to kinases and ATP
Table 7: activity of test Compounds on FGFR mutant enzymes (IC)50，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: BGJ-398 was purchased from Glpbio under catalog number GC 10055.
And (4) 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 Activity for inhibiting proliferation of human gastric cancer cell, bladder cancer cell and liver cancer cell
Using CellTiter-GloTMA live cell assay kit is used for determining the inhibition effect of a test compound A on the proliferation of human gastric cancer cells (SNU-16) with amplified FGFR2 gene, human bladder cancer cells (RT112/84) with high FGFR3 expression and FGFR3-TACC3 fusion and human liver cancer cells (Hep3B) with high FGFR4/FGF19 expression. Among them, the medium for SNU-16 was PRMI-1640 medium (Invitrogen, cat # 11875093) supplemented with 10% final concentration fetal bovine serum and 1% penicillin/streptomycin solution, and the medium for Hep3B cells and RT112/84 cells was EMEM medium (ATCC, cat # 30-2003) supplemented with 10% final concentration fetal bovine serum and 1% penicillin/streptomycin solution.
The test steps are as follows: digesting SNU-16, RT112/84 and Hep3B cells which have reached 80% cell fusion by pancreatin, centrifuging, counting the number of heavy suspensions, preparing SNU-16, RT112/84 and Hep3B cell suspensions with 100000, 20000 and 70000 cells/mL respectively by using culture media, adding 96-well cell culture plates (90 mu L/well), placing in a culture medium containing 5% CO2The cell culture chamber of (2) was cultured at 37 ℃. After 24 hours of cell culture, the reference compound Epirubicin (Epirubicin) and receptorTest compound A was dissolved in DMSO to a concentration of 30mM stock. The diluted compound mother liquor was further diluted with medium of SNU-16, RT112/84 and Hep3B and the diluted mixtures were transferred to respective cell plates at a final concentration of 30. mu.M of test compound (as the starting concentration for the IC50 assay), 5-fold decreasing dilutions of 9 concentrations, 9 concentrations: 30 μ M, 6 μ M, 1.2 μ M, 0.24 μ M, 0.048 μ M, 0.0096 μ M, 0.0019 μ M, 0.0004 μ M and 0.00008 μ M, mixing, centrifuging, placing in a container containing 5% CO2The cells were cultured in the cell culture chamber at 37 ℃ for 3 days. The 96-well cell culture plate was removed, added with CellTiterGlo (CTG, chemiluminescence cell activity assay kit) reagent (100. mu.L/well), mixed well, centrifuged, and incubated at room temperature for 10 minutes. Envision multi-label analyzer readings were used. Calculating the inhibition rate according to the original data, wherein the inhibition rate calculation formula is as follows: inhibition = (DMSO control-test wells)/(DMSO control-medium control) × 100. Performing data analysis by XLFit statistical software, and calculating IC50. The results of the experiment are shown in Table 8.
Table 8: inhibition of SNU-16, RT112/84 and Hep3B cell proliferation by Compound A (IC)50，nM)
| Compound (I) | SNU-16 | RT112/84 | Hep3B |
| Compound A | 5.0 | 2.3 | 5.1 |
| Epirubicin | 274.6 | 75.9 | 451.9 |
Note: epirubicin was purchased from TOCRIS, Cat No. 3260, lot No. 2A 7193516.
And (4) conclusion: the compound A has obvious inhibition effect on the proliferation of tested SNU-16, RT112/84 and Hep3B cells, and the compound A has obvious inhibition effect on the proliferation of tumor cells with abnormal FGFR expression and has better effect than that of a reference compound broad-spectrum anti-cancer drug Epirubicin.
Example 5: evaluation of cell proliferation inhibitory Activity on human bile duct cancer
The MTT method is adopted to determine the inhibition effect of the tested compound A on the proliferation of human bile duct cancer cell HuCCT1 with high FGFR2 expression and human intrahepatic bile duct cancer cell RBE. The cell culture medium used was PRMI-1640 medium supplemented with 10% final concentration of fetal bovine serum (Gibco, lot: 8119264).
The testing steps are as follows: cells in logarithmic growth phase are inoculated in a 96-well plate (100 mu L/well) in a certain quantity, 100 mu L of culture solution containing different concentration gradients of compound A or a control drug TAS-120 is added into each well 24 hours after adherence, each drug concentration is provided with 3 multiple wells, and corresponding blank wells (only culture medium) and normal wells (drug concentration is 0) are arranged. After 72 hours of drug action, MTT working solution (5mg/mL, 20 μ L per well) is added, the mixture is acted for 4 hours at 37 ℃, the supernatant is removed by plate throwing, and 150 μ L DMSO (analytically pure) is added; the plate was wiped clean by shaking with a micropore shaker, and the Optical Density (OD) was measured at 550nm with a microplate reader.
The inhibition rate of cell growth was calculated using the following formula:
inhibition ratio (%) (OD value)Normal holeOD valueMedicine feeding hole) /(OD value)Normal holeOD valueBlank hole)×100％
The half inhibitory concentration of the drug was calculated from the inhibitory rate of each concentration using SPSS19.0Degree IC50. The results of the experiment are shown in Table 9.
Table 9: inhibition of HuCCT1, RBE cell proliferation by Compound A (IC)50，μM)
| Compound (I) | HuCCT1 | RBE |
| Compound A | 1.451±0.464 | 1.068±0.130 |
| TAS-120 | ＞20 | ＞200 |
And (4) conclusion: the compound A has better inhibition effect on tested HuCCT1 and RBE cell proliferation, while TAS-120 has almost no inhibition effect on HuCCT1 and RBE cell proliferation, and has significant difference.
Example 6: in vivo pharmacodynamic evaluation of human gastric cancer SNU-16 cell subcutaneous xenograft tumor BALB/c nude mouse model
The inhibitory effect of the compound A on human gastric cancer is determined by adopting a SNU-16 xenograft tumor BALB/c nude mouse model of the human gastric cancer amplified by the FGFR2 gene.
Cell culture: culturing SNU-16 cells in vitro in RPMI-1640 medium containing 10% fetal calf serum and 2mM L-glutamine at 37 deg.C containing 5% CO2Culturing in an incubator. Conventional digestion twice a week with pancreatin-EDTAAnd (5) carrying out passage. When the saturation degree of the cells is 80% -90% and the quantity 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 solution containing 5X 106A cell suspension of individual SNU-16 cells and a primer (PBS: primer 1: 1(v/v)) was subcutaneously inoculated on the right hind-back of each mouse. On day 13 after inoculation, when the mean tumor volume reached 144mm3Then, the mice were divided into groups of 6 mice each by the stratified randomization method. The reference compound TAS-120 and the test compound A were dissolved in an aqueous solution containing 0.5% (w/v) Methylcellulose (MC) and 0.5% (v/v) Tween 80 to give a solution, and the solution was gavaged at a dose volume of 10mL/kg for 28 days. Tumor diameters were measured twice weekly using a vernier caliper. The formula for tumor volume is: v is 0.5a × b2And a and b represent the major and minor diameters of the tumor, respectively.
The tumor inhibition effect of the compound is expressed by tumor growth inhibition rate (tumor inhibition rate for short) TGI (%). Calculation of TGI (%): TGI (%) × (1- (average tumor volume at the end of administration of a certain treatment group-average tumor volume at the start of administration of the treatment group))/(average tumor volume at the end of treatment in the solvent control group-average tumor volume at the start of treatment in the solvent control group) ] × 100%.
The results of the experiment are shown in Table 10.
Table 10: compound A vs SNU-16 xenograft tumor model tumor volumes (mean. + -. SEM, mm)3N ═ 6) influence
Note: comparisons between two groups were analyzed using T-test, comparisons between three or more groups were analyzed using one-way ANOVA, and data analysis was performed using Prism.
And (4) conclusion: compound a given once daily (QD) at 10, 20 and 40mg/kg doses all had significant anti-tumor effects with a dose-dependent trend. After 28 days of administration, the tumor inhibition rates (TGI) were 63%, 86% and 98%, respectively, and the p-values were all less than 0.05 compared with the solvent control group. Under the same dosage, the tumor inhibition effect of the compound A is better than that of TAS-120, and under the dosage of 40mg/kg, the difference of the curative effects of the compound A and the TAS-120 is obvious, and the compound A has statistical significance (p is less than 0.05).
Example 7: in vivo pharmacodynamic 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 measured by adopting a human bladder cancer cell RT112/84 xenograft tumor BALB/c nude mouse model with high FGFR3 expression and FGFR3-TACC3 fusion.
Cell culture: RT112/84 cells were cultured in vitro in monolayer culture in EMEM medium (Gibco, cat # 11140076) containing 10% fetal bovine serum, 1% NEAA (non-essential amino acids), 2mM L-glutamine at 37 ℃ and 5% CO2Culturing in an incubator. Passage was performed twice a week with conventional digestion treatment with pancreatin-EDTA. When the saturation degree of the cells is 80% -90% and the quantity 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 solution containing 10X 106A cell suspension of RT112/84 cells and a primer (PBS: Matrigel-1: 1(v/v)) was inoculated subcutaneously into the right back of each mouse. When the average tumor volume reaches 188mm3At the same time, the mice were grouped by the hierarchical randomization method, with 8 mice each group. The control compound TAS-120 and the test compound A were dissolved in an aqueous solution containing 0.5% (w/v) MC and 0.5% (v/v) Tween 80 to give a suitable solution, and the solution was gavaged at a dose volume of 10mL/kg to mice for 20 consecutive days. Tumor diameters were measured twice weekly using a vernier caliper. The formula for tumor volume is: v is 0.5a × b2And a and b represent the major and minor diameters of the tumor, respectively.
The antitumor therapeutic effect of the compound was expressed as the tumor growth inhibition rate TGI (%). Calculation of TGI (%): TGI (%) × (1- (average tumor volume at the end of administration of a certain treatment group-average tumor volume at the start of administration of the treatment group))/(average tumor volume at the end of treatment in the solvent control group-average tumor volume at the start of treatment in the solvent control group) ] × 100%.
The results of the experiment are shown in Table 11.
Table 11: compound A vs RT112/84 xenograft tumor model tumor volumes (mean. + -. SEM, mm)3N ═ 8) influence
And (4) conclusion: compound a was administered once daily (QD) at 5, 10 and 20mg/kg doses, all with significant tumor suppression. After 20 days of administration, the tumor inhibition rates (TGI) were 67%, 79% and 83%, respectively, and the p-values were all less than 0.05 compared to the solvent control group. At a dose of 20mg/kg, compound A had a comparable anti-tumor effect to TAS-120.
Example 8: in vivo pharmacodynamic evaluation of human liver cancer LI-03-0332 subcutaneous xenograft model
The subcutaneous transplantation tumor model constructed by nude mice after inoculation of high-expression FGFR3 LI-03-0332 human liver cancer tissues is adopted to determine the inhibition effect of the compound A on human liver cancer.
Tumor tissue: establishment of the human liver cancer LI-03-0332 model was originally derived from a clinical specimen excised by surgery. The collection of specimens is carried out in strict compliance with national, hospital and company ethical laws and regulations. The passage naming rule is as follows: the tumor sample is inoculated to a nude mouse and then is P0 generations, the tumor sample is continuously passaged to P1 generations, and by analogy, the recovered sample is named as FP, and the tumor tissue used in the experiment is FP9 generations.
The test steps are as follows: removing necrotic tissue from LI-03-0332 tumor tissue, and cutting into pieces of 20-30mm3After the substrate gel is added to the small blocks, the liver cancer tumor tissues are inoculated to the right back of each mouse subcutaneously, and 149 mice are inoculated in total. On day 22 post-inoculation, the mean tumor volume was measured to reach 135mm3In the preparation process, the mice are divided into groups according to the tumor volume and the animal weight by adopting a random layering and grouping method, 6 mice in a solvent control group are adopted, and 8 mice in each group are adopted in the other groups. The control compound TAS-120 and the test compound A were dissolved in an aqueous solution containing 0.5% (w/v) MC and 0.5% (v/v) Tween 80 to give a suitable solution, and the solution was gavaged at a dose volume of 10mL/kg to mice for 21 consecutive days. Twice weekly vernierCalipers measure tumor diameter. The formula for tumor volume is: v is 0.5a × b2And a and b represent the major and minor diameters of the tumor, respectively.
The antitumor effect of the compound is represented by the tumor growth inhibition rate TGI (%). Calculation of TGI (%): TGI (%) × (1- (average tumor volume at the end of administration of a certain treatment group-average tumor volume at the start of administration of the treatment group))/(average tumor volume at the end of treatment in the solvent control group-average tumor volume at the start of treatment in the solvent control group) ] × 100%.
The results of the experiment are shown in Table 12.
Table 12: compound A vs LI-03-0332 xenograft tumor model tumor volumes (mean. + -. SEM, mm)3) Influence of (2)
Note: the solvent control group contained 6 animals, and the other groups 8 animals.
And (4) conclusion: compound a was administered once daily (QD) at 5, 10 and 20mg/kg doses, all with significant tumor suppression. After 21 days of administration, the tumor inhibition rates (TGI) were 81%, 79% and 87%, respectively, and the p-values were all less than 0.0001 compared with the solvent control group. At a dose of 20mg/kg, compound A had a comparable anti-tumor effect to TAS-120.
Example 9: evaluation of off-target Effect on important kinases
The inhibition effect of the compound A on the activity of various non-target kinases is analyzed by utilizing an Enzyme Profiling Services technical platform of eurofins company. Compounds detection of each Kinase Using the Eurofins Standard Kinase ProfileTMExperimental procedures, which follow the relevant standard operating procedures. Protein kinase (except ATM (h) and DNA-PK (h)) assays were assayed by radiation dose, while lipid kinase, ATM (h), ATR/ATRIP (h), and DNA-PK (h) assays were assayed by
And (6) detecting.
The test steps are as follows: taking a proper amount of 50 times of working solution (dissolved in 100% DMSO) of a test compound A into a test hole (the final concentration of the compound A is 0.1 mu M), and then adding a uniformly 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 results of the experiment are shown in Table 13.
Table 13: evaluation results of miss Effect
And (4) conclusion: at a concentration of 0.1. mu.M, Compound A had no significant inhibition of more than 50 kinases tested.
Example 10: evaluation of safety pharmacology
The effect of a single gavage administration of test compound a on central nervous system function in SD rats was evaluated using a functional observational combined test (FOB). 20 rats each male and female were divided into 4 groups of 5 rats each, and vehicle (aqueous solution containing 0.5% (weight/volume, w/v) methylcellulose and 0.2% (w/v) tween 80) or compound a was administered orally at doses of 0.5, 1.2 and 3 mg/kg. All animals were dosed in a volume of 5 mL/kg. In this test, 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. The observation metrics include motor function, behavioral changes, coordination function, sensory/motor reflexes, and body temperature. As a result, no change was observed at each observation time point in relation to the test article. Under the conditions of this test, no effect of the test compound A on the central nervous system of rats was observed.
The effect of oral gavage of test compound a on the cardiovascular parameters of conscious beagle dogs was evaluated using telemetry. Male and female 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 a dose of test Compound A of 0.3, 0.6 or 2 mg/kg. Animals were observed daily for survival. Cage-side observations were performed 2 times per day on non-dosing days, with detailed clinical observations performed before and after each dose. Electrocardiograms, heart rate and blood pressure were recorded continuously for all experimental animals from at least 2 hours before each administration to about 24 hours after administration. Electrocardiographic waveforms of about 30 seconds length were printed at 2 time points before dosing (at least 30 minutes apart) and 6 time points after dosing (0.5 hour, 1 hour, 2 hours, 4 hours, 12 hours, and 24 hours after dosing) for each dose. The results show that, under the test conditions, no change in cardiovascular index associated with the test article was observed in beagle dogs upon single oral gavage of test compound a at doses of 0.3, 0.6 and 2mg/kg within 24 hours after administration.
The SD rats were given test compound a by single oral gavage and their effect on respiratory function was evaluated. Each 20 rats in males and females are divided into 4 groups of 5 rats in each group, and a control formulation (vehicle: containing 0.5% (w/v) methylcellulose and 0.2% (w/v) aqueous Tween 80) or 0.5, 1.2 or 3mg/kg of test Compound A is administered orally. All animals were dosed in a volume of 5 mL/kg. Prior to dosing, respiratory data (tidal volume, respiratory rate, minute ventilation) was collected for approximately 15 minutes as a pre-group respiratory parameter baseline. The time points collected on the day of administration were data collected for approximately 15 consecutive minutes each before administration, 2 hours after administration, 8 hours after administration, and 24 hours after administration. The results show that 24 hours after a single oral administration, no effect of the test article on rat respiratory rate, tidal volume and minute ventilation was observed.
The results of the experiment are shown in Table 14.
Table 14: safety pharmacological test results
And (4) conclusion: the compound A has no influence on the central nervous system and respiratory system of SD rats and the cardiovascular system of beagle dogs, and the compound A is high in safety.
Example 11: acute toxicity test
1. Single-time gavage toxicity test in rats
The test method comprises the following steps: 40 rats were randomly divided into 4 groups of 10 rats each, each half of males and females, and administered compound A and a control solvent, respectively, in a single oral gavage, 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, to test the maximum tolerated dose of compound A. The administration volume was 10mL/kg and the observation period was 14 days.
And (3) test results: a slight increase in yellow abnormal stool and total bilirubin was observed only in the 400mg/kg dose group. No significant difference in test article-related death, clinical symptoms, macroscopic lesions, weight change, food intake and clinical tests (hematology, hemagglutination, serum biochemistry and urinalysis) is found in the male and female animals of other dose groups compared with the solvent control group. Thus, the Maximum Tolerated Dose (MTD) for a single administration under the conditions of this test was 400 mg/kg.
2. Single gavage toxicity test for dogs
The test method comprises the following steps: 8 beagle dogs, randomly divided into 4 groups of 2 dogs each, hermaphrodite halves, were given a single oral gavage of compound A at 15, 50 or 250mg/kg, respectively, and a control solvent in the form of an aqueous solution containing 0.5% (w/v) MC and 0.2% (w/v) Tween 80. The administration volume was 5 mL/kg. Animals were fasted overnight prior to dosing. The observation period was 14 days. The males and females were necropsied on day 21.
And (3) test results: a single gavage of 15, 50 or 250mg/kg compound a in beagle dogs did not produce test-related mortality, clinical symptoms, body weight, food intake, hematology, blood clotting, serum biochemistry, urinalysis parameters, macroscopic lesions, and histopathological adverse reactions. Therefore, the Maximum Tolerated Dose (MTD) of the male and female beagle dogs under the test conditions was considered to be 250 mg/kg.
And (4) conclusion: the compound A has higher tolerance dose in single-time gastric lavage administration toxicity test and good safety.
Various aspects of the present invention have been illustrated by the above-described embodiments. It should be understood that the above-described embodiments are given for illustrative purposes only, and are not intended to limit the scope of the present invention in any way. Other variations and modifications in the form of the above examples will be apparent to those skilled in the art. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications derived therefrom are within the scope of the invention.
Claims (10)
- Use of an FGFR inhibitor compound a or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of an FGFR-associated tumor, wherein the compound a has the following structure:
- the use of claim 1, wherein the FGFR-related tumor is one or more of a digestive or urological tumor; preferably any one or any combination of gastric cancer, liver cancer, urothelial cancer, and bile duct cancer.
- The use of claim 2, wherein the liver cancer is any one of hepatocellular carcinoma, intrahepatic cholangiocellular carcinoma, 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, hepatic portal bile duct cancer and distal bile duct cancer, and is preferably intrahepatic bile duct cancer.
- The use according to any one of claims 1-3, wherein 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.
- Use according to any one of claims 1-3, wherein the medicament is formulated as a clinically acceptable formulation, preferably an oral formulation, an injectable formulation or an external formulation.
- The use according to any one of claims 1-3, wherein the Compound A or the pharmaceutically acceptable salt thereof is administered at a daily dosage range of 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, even further preferably from about 0.03mg/kg to about 20 mg/kg.
- The use according to any one of claims 1-3, wherein the medicament contains a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.
- Use according to claim 7, wherein the therapeutically effective amount is 0.001-1000mg, preferably 0.01-100mg, further preferably 0.1-50mg, even further preferably 0.5-30 mg.
- The use of any one of claims 1-3, wherein the Compound A or pharmaceutically acceptable salt thereof is administered in a single dose or in divided doses.
- Use according to any one of claims 1-3, wherein the medicament is administered orally, by injection, topically or in vitro, preferably by oral administration or injection.
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