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

  • J Med Chem. 2026 May 14;69(9):10104-10121. doi: 10.1021/acs.jmedchem.5c03074.
Yu Zhang  1  2 ,  Pengfei Wang  2  3 ,  Zhicheng Xie  1  2 ,  Yilun Huang  1  2 ,  Yaqi Ding  2  3 ,  Jia Liu  1  2  4 ,  Yi Chen  2  3 ,  Youhong Hu  1  2  4  5
Affiliations
  • 1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu-ChongZhi Road, Shanghai 201203, China.
  • 2. University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
  • 3. State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 4. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1st Xiangshan Branch Alley, Hangzhou 310024, China.
  • 5. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China.
PMID: 42024642 DOI: 10.1021/acs.jmedchem.5c03074
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.

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