Huimin Zhang, Dounan Xu, Hongchan Huang, Hao Jiang, Linghao Hu, Liping Liu, Ge Sun, Jing Gao, Yuanqing Li, Cuicui Xia, Shijie Chen, Hu Zhou, Xiangqian Kong, Mingliang Wang, Cheng Luo
Nonreceptor tyrosine kinase c-Src plays a crucial role in cell signaling and contributes to tumor progression. However, the development of selective c-Src inhibitors turns out to be challenging. In our previous study, we performed posttranslational modification-inspired drug design (PTMI-DD) to provide a plausible way for designing selective kinase inhibitors. In this study, after identifying a unique pocket comprising a less conserved cysteine and an autophosphorylation site in c-Src as well as a promiscuous covalent inhibitor, chemical optimization was performed to obtain ( R )-LW-Srci-8 with nearly 75-fold improved potency (IC50 = 35...
March 21, 2024: ACS Chemical Biology