可药性
激酶
计算生物学
药物发现
抗药性
生物
生物信息学
生物化学
遗传学
基因
作者
Jing Guo,Yang Zhou,Xiaoyun Lu
标识
DOI:10.1080/17460441.2023.2265303
摘要
Acquired resistance caused by gatekeeper mutations has become a major challenge for approved kinase inhibitors used in the clinic. Consequently, the development of new-generation inhibitors or degraders to overcome clinical resistance has become an important research focus for the field.This review summarizes the common gatekeeper mutations in druggable kinases and the constantly evolving inhibitors or degraders designed to overcome single or double mutations of gatekeeper residues. Furthermore, the authors provide their perspectives on the medicinal chemistry strategies for addressing clinical resistance with gatekeeper mutations.The authors suggest optimizing kinase inhibitors to interact effectively with gatekeeper residues, altering the binding mode or binding pocket to avoid steric clashes, improving binding affinity with the target, utilizing protein degraders, and developing combination therapy. These approaches have the potential to be effective in overcoming resistance due to gatekeeper residues.
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