化学
甲酰胺
吡唑
共价键
化学合成
组合化学
酶抑制剂
立体化学
生物化学
体外
有机化学
作者
Wuqing Deng,Xiaojuan Chen,Hong Liang,Xiaojuan Song,Shuang Xiang,Jing Guo,Zhengchao Tu,Yang Zhou,Yongheng Chen,Xiaoyun Lu
标识
DOI:10.1016/j.ejmech.2024.116558
摘要
The aberrant activation of FGFRs plays a critical role in various cancers, leading to the development of several FGFR inhibitors in clinic. However, the emergence of drug resistance, primarily due to gatekeeper mutations in FGFRs, has limited their clinical efficacy. To address the unmet medical need, a series of 5-amino-1H-pyrazole-4-carboxamide derivatives were designed and synthesized as novel pan-FGFR covalent inhibitors targeting both wild-type and the gatekeeper mutants. The representative compound 10h demonstrated nanomolar activities against FGFR1, FGFR2, FGFR3 and FGFR2 V564F gatekeeper mutant in biochemical assays (IC
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