2. Academic Validation
  3. 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

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

  • Eur J Med Chem. 2018 Jan 1:143:1148-1164. doi: 10.1016/j.ejmech.2017.09.018.
Jiao Yang 1,  Kai Chen 1,  Guo Zhang 2,  Qiu-Yuan Yang 1,  Yue-Shan Li 1,  Shen-Zhen Huang 1,  Yan-Lin Wang 1,  Wei Yang 2,  Xiao-Juan Jiang 1,  Heng-Xiu Yan 1,  Jing-Qiang Zhu 1,  Rong Xiang 3,  You-Fu Luo 1,  Wei-Min Li 1,  Yu-Quan Wei 1,  Lin-Li Li 4,  Sheng-Yong Yang 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan 610041, China.
  • 2 Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Sichuan 610041, China.
  • 3 Department of Clinical Medicine, School of Medicine, Nankai University, Tianjin 300071, China.
  • 4 Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Sichuan 610041, China. Electronic address: ysylilinli@sina.com.
  • 5 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan 610041, China. Electronic address: yangsy@scu.edu.cn.
PMID: 29133048 DOI: 10.1016/j.ejmech.2017.09.018
Abstract

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.

Keywords

Drug resistance mutant; Medullary thyroid cancer; RET kinase; Structure-activity relationship.

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