Discovery and Optimization of the First ATP Competitive Type-III c-MET Inhibitor

作者：Iacovos N. Michaelides, Gavin W. Collie, Ulf Börjesson, Christina Vasalou, Omar Alkhatib, Louise Barlind, Tony Cheung, Ian L. Dale, Kevin J. Embrey, Edward J. Hennessy, Puneet Khurana, Cheryl M. Koh, Michelle L. Lamb, Jianming Liu, Tom Moss, Daniel O’Neill, Christopher Phillips, Joseph Shaw, Arjan Snijder, Richard Storer, Christopher J. Stubbs, Fujin Han, Chengzhi Li, Jingchuan Qiao, Dongqing Sun, Jingwen Wang, Peng Wang, Wenzhen Yang · 发表于：Journal of Medicinal Chemistry · 年份：2023 · DOI：10.1021/acs.jmedchem.3c00401 · 被引用次数：23 · 研究领域：Enzyme function and inhibition、PI3K/AKT/mTOR signaling in cancer、Synthesis and biological activity

High Resolution Image Download MS PowerPoint Slide Recent clinical reports have highlighted the need for wild-type (WT) and mutant dual inhibitors of c-MET kinase for the treatment of cancer. We report herein a novel chemical series of ATP competitive type-III inhibitors of WT and D1228V mutant c-MET. Using a combination of structure-based drug design and computational analyses, ligand 2 was optimized to a highly selective chemical series with nanomolar activities in biochemical and cellular settings. Representatives of the series demonstrate excellent pharmacokinetic profiles in rat in vivo studies with promising free-brain exposures, paving the way for the design of brain permeable drugs for the treatment of c-MET driven cancers.