Discovery of 2H-Pyrrolo[3,4‑c]pyridin-3-one Derivatives as Type-III c‑MET Inhibitors Enabled by Free-Energy Perturbation Calculations.

Eric Therrien¹, Shulu Feng¹, Katherine Amberg-Johnson¹, Nadim Shaikh², Pradeep Patil², Sarmistha Majumdar², Nikita Abraham², Daniel Eiler³, Steffen Kutter³, Steven K Albanese¹, Susanta Haldar², Kyle G Kroeck³, Christian Atsriku¹, Aleksey I Gerasyuto¹, Adam M Levinson¹

¹Schrödinger Inc., New York, New York, 10036, United States.

²Schrödinger Inc., Hyderabad, 500081, Telangana, India.

³Schrödinger Inc., Framingham, Massachusetts 01702, United States.

PubMed PMC DOI PDF

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…

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