Yang, Jiao; Chen, Kai; Zhang, Guo; Yang, Qiu-Yuan; Li, Yue-Shan; Huang, Shen-Zhen; Wang, Yan-Lin; Yang, Wei; Jiang, Xiao-Juan; Yan, Heng-Xiu; Zhu, Jing-Qiang; Xiang, Rong; Luo, You-Fu; Li, Wei-Min; Wei, Yu-Quan; Li, Lin-Li; Yang, Sheng-Yong published the artcile< 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>, Application In Synthesis of 22280-62-2, the main research area is phenyldihydro pyrimido oxazinamine derivative preparation RET inhibitor cancer; Drug resistance mutant; Medullary thyroid cancer; RET kinase; Structure-activity relationship.
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-6H-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 IC50 (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, resp. 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 immunohistochem. assays. Collectively, 17d could be a promising agent for the treatment of MTC, hence deserving a further investigation.
European Journal of Medicinal Chemistry published new progress about Antitumor agents. 22280-62-2 belongs to class pyridine-derivatives, and the molecular formula is C6H7N3O2, Application In Synthesis of 22280-62-2.