11HQ

Type-III c-MET Inhibitor Enabled by Free-Energy Perturbation Calculations

This is a non-PDB format compatible entry.

Summary for 11HQ

• Entry DOI: 10.2210/pdb11hq/pdb
• Descriptor: Hepatocyte growth factor receptor, (1R,6M)-1-benzyl-6-[(3P)-3-(1-ethyl-1H-pyrazol-4-yl)-5-fluorophenyl]-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (3 entities in total)
• Functional Keywords: tyrosine kinase, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 3
• Total formula weight: 105983.48

Authors

Eiler, D.R.,Abraham, N.,Kutter, S.,Kroeck, K.G. (deposition date: 2026-02-25, release date: 2026-05-27, Last modification date: 2026-07-01)

Primary citation

Therrien, E.,Feng, S.,Amberg-Johnson, K.,Shaikh, N.,Patil, P.,Majumdar, S.,Abraham, N.,Eiler, D.,Kutter, S.,Albanese, S.K.,Haldar, S.,Kroeck, K.G.,Atsriku, C.,Gerasyuto, A.I.,Levinson, A.M.
Discovery of 2H-Pyrrolo[3,4‐ c ]pyridin-3-one Derivatives as Type-III c‐MET Inhibitors Enabled by Free-Energy Perturbation Calculations.
Acs Med.Chem.Lett., 17:1364-1372, 2026

PubMed Abstract: The clinical emergence of diverse c-MET mutations with resistance to approved inhibitors has created an urgent demand for next-generation inhibitors with efficacy against c-MET-resistant mutations while maintaining c-MET wild-type (WT) potency, selectivity over other kinases, and brain penetration. Here, we report a novel chemical series discovered through iterative core enumeration and decoration guided by free energy perturbation calculations. Type-III inhibitor demonstrated potent activity against both WT and c-MET with the D1228V resistance mutation with promising physicochemical properties, laying the foundation for the development of brain-penetrant therapies targeting c-MET-driven cancers.

PubMed: 42305208
DOI: 10.1021/acsmedchemlett.6c00158

Experimental method

X-RAY DIFFRACTION (2.65 Å)