期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 244, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2022.114862
关键词
REarranged during Transfection (RET) kinase; Solvent-front mutation; Resistance; Structure-based design; Inhibitors
资金
- High-Performance Public Computing Service Platform of Jinan University
- National Natural Science Foundation of China [81874284, 22037003, 81820108029, 8182010804, 81973158]
- Ministry of Science and Technology of the People's Republic of China [SQ2019YFE0197900]
- Natural Science Foundation of Guangdong Province [2018B030337001, 2022A1515011020]
- Shenzhen Bay Laboratory Open Fund [SZBL2021080601004]
- Open Project of State Key Laboratory of Esophageal Cancer Prevention and Treatment (Zhengzhou University) [K2022-010]
A newly designed RET kinase inhibitor was found to effectively suppress resistant mutants and exhibit significant anti-tumor efficacy in cell and mouse models.
REarranged during Transfection (RET) is a validated target for anticancer drug discovery and two selective RET inhibitors were approved by US FDA in 2020. However, acquired resistance mediated by secondary mutations in the solvent-front region of the kinase (e.g. G810C/S/R) becomes a major challenge for selective RET inhibitor therapies. Herein, we report a structure-based design of 1-methyl-3-((4-(quinolin-4-yloxy)phenyl)amino)-1H- pyrazole-4-carboxamide derivatives as new RET kinase inhibitors which are capable of suppressing the RETG810 C/R resistant mutants. One of the representative compounds, 8q, potently suppressed wild-type RET kinase with an IC50 value of 13.7 nM. It also strongly inhibited the proliferation of BaF3 cells stably expressing various oncogenic fusions of RET kinase with solvent-front mutations, e.g. CCDC6-RETG810C, CCDC6-RETG810R, KIF5B-RETG810C and KIF5B-RETG810R, with IC50 values of 15.4, 53.2, 54.2 and 120.0 nM, respectively. Furthermore, 8q dose-dependently inhibited the activation of RET and downstream signals and obviously triggered apoptosis in Ba/F3-CCDC6-RETG810 C/R cells. The compound also exhibited significant anti-tumor efficacy with a tumor growth inhibition (TGI) value of 66.9% at 30 mg/kg/day via i. p. in a Ba/F3-CCDC6-RETG810C xenograft mouse model. Compound 8q may be utilized as a lead compound for drug discovery combating acquired resistance against selective RET inhibitor therapies.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据