European Journal of Medicinal Chemistry p. 1148 - 1164 (2018)
Update date:2022-08-30
Topics:
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
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, 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.
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Doi:10.1039/a801147h
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