Abstact

Mesenchymal-epithelial transition factor (c-Met) is a receptor tyrosine kinase belonging to the MET gene family. Aberrant c-Met signaling drives tumorigenesis. Acquired drug resistance to current type I c-Met inhibitors has limited their duration of response. Many type II inhibitors have been developed to address the on-target resistance mutations that render type I inhibitors ineffective. However, type II inhibitors, to date, have not been approved to treat c-Met-driven cancers due to poor selectivity and suboptimal physicochemical properties that limit free drug concentrations. Herein, we describe how structure-based drug design (SBDD) directed at optimization of lipophilic efficiency (LipE) enabled the discovery of a highly selective type IIb c-Met inhibitor with quality drug-like properties. Lead compound KIN-8741 exhibits broad potency against acquired resistance mutations and a desirable safety profile that supported the filing and clearance of an IND for the treatment of cancer.