化学
体外
克拉斯
激酶
突变体
IC50型
酶
效力
MAPK/ERK通路
药物发现
药理学
生物化学
癌症研究
突变
生物
基因
作者
Peng Zhao,Xiangzhu Wang,Liujing Zhuang,Song Huang,Yu Zhou,Yuna Yan,Ru Shen,Fan Zhang,Jie Li,Qiyue Hu,Suxing Liu,Rumin Zhang,Ping Dong,Hong Wan,Chang Bai,Feng He,Weikang Tao
标识
DOI:10.1016/j.bmcl.2022.128666
摘要
The development of RAF inhibitors targeting cancers with wild type RAF kinase and/or RAS mutation has been challenging due to the paradoxical activation of the RAS-RAF-MEK-ERK cascade following RAF inhibitor treatment. Herein is the discovery and optimization of a series of RAF inhibitors with a novel spiro structure. The most potent spiro molecule 9 showed excellent in vitro potency against b/c RAF enzymes and RAS mutant H358 cancer cells with minimal paradoxical RAF signaling activation. Compound 9 also exhibited good drug-like properties as demonstrated by in vitro cytochrome P450 (CYP), liver microsome stability (LMS) data and moderate oral pharmacokinetics (PK) profiles in rat and mouse.
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