Year: 2025
Type: article
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 (IC 50 = 20 nM) and significantly enhanced antiproliferative activity (IC 50 = 10 nM against HAP1MTAP –/– cells). Moreover, compound 9 exhibited improved selectivity compared to both AZ-28 and AG-270 .
Source: ACS Medicinal Chemistry Letters
Authors: Yushan Zhou, Li Wang, Ruyue Ren, Junjie Zhang, Xiajuan Huan, Peng Yang, Ze-Hong Miao, Bing Xiong, Yingqing Wang, Tongchao Liu
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W4408477752