8VI1

Crystal structure of c-Met-D1228N in complex with KIN-7615

This is a non-PDB format compatible entry.

Summary for 8VI1

• Entry DOI: 10.2210/pdb8vi1/pdb
• Descriptor: Hepatocyte growth factor receptor, N-(3,5-difluoro-4-{[6-(2-hydroxyethoxy)-7-methoxyquinolin-4-yl]oxy}phenyl)-4-methoxypyridine-3-carboxamide (2 entities in total)
• Functional Keywords: c-met d1228n kin-7615, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 70677.56

Authors

Ouyang, X.,Kania, R.,Cox, J. (deposition date: 2024-01-02, release date: 2025-04-02, Last modification date: 2025-06-25)

Primary citation

Ouyang, X.S.,Grandinetti, K.B.,Boren, M.,Chakravorty, S.,Chopade, S.,Jiang, P.,Kanouni, T.,Koudriakova, T.,Makwana, O.,Pack, S.K.,Perez, M.,Suriben, R.,Timple, N.,Thohan, S.,Uryu, S.,Womble, S.,Yuan, D.,Kania, R.S.,Cox, J.M.
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., 68:10648-10662, 2025

PubMed 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 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.

PubMed: 40459881
DOI: 10.1021/acs.jmedchem.5c00834

Experimental method

X-RAY DIFFRACTION (3.11 Å)