Structure-Based Discovery of a Series of Novel MAT2a Inhibitors
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 <b>AZ-28</b> in complex with the MAT2a dimer, compound <b>9</b> was synthesized, demonstrating potent MAT2a inhibition (IC<sub>50</sub> = 20 nM) and significantly enhanced antiproliferative activity (IC<sub>50</sub> = 10 nM against HAP1MTAP<sup>-/-</sup> cells). Moreover, compound <b>9</b> exhibited improved selectivity compared to both <b>AZ-28</b> and <b>AG-270</b>.
Authors
- Ruiyi Ren (ORCID: https://orcid.org/0000-0001-5785-2165)
- Bing Xiong (ORCID: https://orcid.org/0000-0001-9776-8136)
- Ze-Hong Miao
- Tongchao Liu (ORCID: https://orcid.org/0000-0003-0896-5854)
- Peng Yang (ORCID: https://orcid.org/0000-0001-5328-6266)
- Ying-Qing Wang
- Xia‐Juan Huan
- Li Wang (ORCID: https://orcid.org/0000-0002-8686-6627)
- Junjie Zhang (ORCID: https://orcid.org/0000-0003-3812-3850)
- Yushan Zhou (ORCID: https://orcid.org/0009-0002-7166-1191)
Institutions
- Shenyang Pharmaceutical University (CN)
- Shanxi Medical University (CN)
- Chinese Academy of Sciences (CN)
- Shanghai Institute of Materia Medica (CN)
- State Key Laboratory of Chemical Engineering (CN)
- University of Chinese Academy of Sciences (CN)
Publication Details
- Journal
- ACS Medicinal Chemistry Letters
- Published
- 2025-03-15
- DOI
- https://doi.org/10.1021/acsmedchemlett.5c00049
- Citations
- 2
- Primary Topic
- Protein Tyrosine Phosphatases
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- National Natural Science Foundation of China
- Chinese Academy of Sciences