Structure-Based Discovery of a Series of Novel MAT2a Inhibitors

  • ACS Med Chem Lett. 2025 Mar 15;16(4):646-650. doi: 10.1021/acsmedchemlett.5c00049.
Yushan Zhou  1  2  3 ,  Li Wang  4  5 ,  Ruyue Ren  2  3  6 ,  Junjie Zhang  2  3  5 ,  Xiajuan Huan  4 ,  Peng Yang  1 ,  Ze-Hong Miao  4  5 ,  Bing Xiong  2  3  5 ,  Yingqing Wang  4  5 ,  Tongchao Liu  2  3
Affiliations
  • 1. Wuya College of Innovation, Shenyang Pharmaceutical University,103 Wenhua Road, Shenyang, Liaoning 110016, P. R. China.
  • 2. Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P. R. China.
  • 3. State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China.
  • 4. State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, P. R. China.
  • 5. University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, P. R. China.
  • 6. School of Pharmacy, Shanxi Medical University, Taiyuan 030001, P. R. China.
PMID: 40236535 DOI: 10.1021/acsmedchemlett.5c00049
Abstract

Methionine adenosyltransferase 2a (MAT2a) has emerged as a promising therapeutic target due to its role in the synthetic lethality mechanism associated with MTAP-deficient tumors. In this study, we describe our efforts to identify a novel series of MAT2a inhibitors through a fragment-based joining strategy, leading to the development of a single molecule that occupies the allosteric site of the MAT2a dimer. Guided by the costructure of AZ-28 in complex with the MAT2a dimer, compound 9 was synthesized, demonstrating potent MAT2a inhibition (IC50 = 20 nM) and significantly enhanced antiproliferative activity (IC50 = 10 nM against HAP1MTAP-/- cells). Moreover, compound 9 exhibited improved selectivity compared to both AZ-28 and AG-270.

Products