2. Academic Validation
  3. Discovery of KIN-8741, a Highly Selective Type IIb c-Met Kinase Inhibitor with Broad Mutation Coverage and Quality Drug-Like Properties for the Treatment of Cancer

Discovery of KIN-8741, a Highly Selective Type IIb c-Met Kinase Inhibitor with Broad Mutation Coverage and Quality Drug-Like Properties for the Treatment of Cancer

  • J Med Chem. 2025 Jun 12;68(11):10648-10662. doi: 10.1021/acs.jmedchem.5c00834.
Xiaohu S Ouyang 1,  Kathryn B Grandinetti 1,  Morgan Boren 1,  Subhas Chakravorty 1,  Shubham Chopade 1,  Ping Jiang 1,  Toufike Kanouni 1,  Tatiana Koudriakova 1,  Om Makwana 1,  Shawn K Pack 1,  Michelle Perez 1,  Rowena Suriben 1,  Noel Timple 1,  Sanjeev Thohan 1,  Sean Uryu 1,  Scott Womble 1,  Ding Yuan 1,  Robert S Kania 1,  Jason M Cox 1
Affiliations

Affiliation

  • 1 Kinnate Biopharma Inc., San Diego, California 92130, United States.
PMID: 40459881 DOI: 10.1021/acs.jmedchem.5c00834
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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