Discovery, Optimization, and Evaluation of Novel Pyridin-2(1)-one Analogues as Potent TRK Inhibitors for Cancer Treatment.

Tropomyosin receptor kinase (TRK) fusion, an oncogenic form of kinase with pan-tumor occurrence, is a clinically validated important antitumor target. In this study, we screened our in-house kinase inhibitor library against TRK and identified a promising hit compound with a novel pyridin-2(1)-one scaffold. Through a combination of structure-based drug design and structure-activity relationship (SAR) study, compound was identified as a potent TRK inhibitor with good kinase selectivity. It also blocked cellular TRK signaling, thereby inhibiting TRK-dependent cell viability. Additionally, displayed acceptable pharmacokinetic properties with 37.8% oral bioavailability in mice. Strong tumor growth inhibition of was observed in subcutaneous M091 and KM12 tumor xenograft models with TRK fusion, causing significant tumor inhibition or even complete tumor regression.