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Updated: Jun 13, 2025

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
Discovery of KIN-8741, a Highly Selective Type IIb c-Met Kinase Inhibitor with Broad Mutation Coverage and Quality
Xiaohu S Ouyang1, Kathryn B Grandinetti1, Morgan Boren1
1Kinnate Biopharma Inc., San Diego, California 92130, United States.
Abstract:
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.
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