Structural optimization and structure-activity relationship studies of N-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine derivatives as a new class of inhibitors of RET and its drug resistance mutants
| Autor: | Rong Xiang, Jiao Yang, Weimin Li, Shengyong Yang, Yuquan Wei, Xiao-Juan Jiang, Wei Yang, Lin-Li Li, Jingqiang Zhu, Y. Li, Shenzhen Huang, Kai Chen, Youfu Luo, Heng-Xiu Yan, Guo Zhang, Qiuyuan Yang, Yanlin Wang |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
endocrine system endocrine system diseases Cell Survival Mutant Antineoplastic Agents Mice SCID Drug resistance Mice Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Western blot Mice Inbred NOD In vivo Drug Discovery medicine Animals Structure–activity relationship Amines Cells Cultured Cell Proliferation Pharmacology Dose-Response Relationship Drug Molecular Structure medicine.diagnostic_test Chemistry Kinase Proto-Oncogene Proteins c-ret Organic Chemistry Medullary thyroid cancer Neoplasms Experimental General Medicine medicine.disease Molecular biology 030104 developmental biology Biochemistry Drug Resistance Neoplasm 030220 oncology & carcinogenesis Mutation NIH 3T3 Cells Drug Screening Assays Antitumor Tyrosine kinase |
| Zdroj: | European Journal of Medicinal Chemistry. 143:1148-1164 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2017.09.018 |
| Popis: | The RET tyrosine kinase is an important therapeutic target for medullary thyroid cancer (MTC), and drug resistance mutations of RET, particularly V804M and V804L, are a main challenge for the current targeted therapy of MTC based on RET inhibitors. In this investigation, we report the structural optimization and structure-activity relationship studies of N -phenyl-7,8-dihydro-6 H -pyrimido[5,4-b][1,4]oxazin-4-amine derivatives as a new class of RET inhibitors. Among all the obtained kinase inhibitors, 1-(5-( tert -butyl)isoxazol-3-yl)-3-(4-((6,7,8,9-tetrahydropyrimido[5,4-b][1,4]oxazepin-4-yl)amino)phenyl)urea ( 17d) is a multi-kinase inhibitor and potently inhibits RET and its drug resistance mutants. It showed IC 50 (half maximal inhibitory concentration) values of 0.010 μM, 0.015 μM, and 0.009 μM against RET-wild-type, RET-V804M, and RET-V804L, respectively. 17d displayed significant anti-viability potencies against various RET-driving tumor cell lines. In a xenograft mouse model of NIH3T3-RET-C634Y, 17d exhibited potent in vivo anti-tumor activity, and no obvious toxicity was observed. Mechanisms of action were also investigated by Western blot and immunohistochemical assays. Collectively, 17d could be a promising agent for the treatment of MTC, hence deserving a further investigation. |
| Databáze: | OpenAIRE |
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