Discovery of pyrido[4,3-d]pyrimidinone derivatives as novel Wee1 inhibitors

Wee1 has emerged as a potential target in cancer therapy due to its critical role in the regulation of the cell cycle. Here, we describe a series of Wee1 inhibitors with a novel scaffold that are potent inhibitors of this kinase (IC₅₀ = 19-1485 nM). These inhibitors demonstrated robust cytotoxicity in MV-4-11 and T47D cell lines (MV-4-11 IC₅₀ = 660-2690 nM, T47D IC₅₀ = 2670-20,000 nM) and displayed good stability in mouse liver microsomes in vitro. Additionally, compound 34 showed remarkable selectivity (more than 500-fold) over the other 9 kinases. Further mechanistic studies demonstrated that compound 34 displayed measurable effects on downstream biomarkers and induced cancer cell apoptosis and cell cycle arrest in the G0/G1 phase. Taken together, these results show that compound 34, potentially a leading Wee1 inhibitor, warrants further investigation.