Abstract

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 strong cellular activity in HCT-116 MTAP KO cells (GI50 = 0.76 μM). Moreover, 33 retained high potency in MTAP-naturally deficient cancer cell lines. In vivo, 33 demonstrated favorable pharmacokinetic properties and induced pronounced antitumor efficacy in the NCI-H838 xenograft model with minimal toxicity. Mechanically, treatment with 33 markedly reduced SAM and sDMA levels both in vitro and in vivo. Collectively, these results establish pyridazinone as a privileged scaffold for MAT2A inhibition and identify compound 33 as a compelling lead for further preclinical development.