Design and Discovery of Pyridazinone-Based MAT2A Inhibitors Targeting MTAP-Deficient Cancers

In cancers with MTAP deletions, MAT2A inhibition has emerged as a promising therapeutic strategy in cancer treatment through a synthetic mechanism. Herein, we report the design and optimization of a novel series of pyridazinone-based MAT2A inhibitors via a ring-opening strategy from AGI-41998. Through iterative structure-activity relationship (SAR) studies, compound 33 was identified as the lead compound, displaying potent MAT2A inhibition (IC₅₀ = 17.5 nM) and str