基于结构的一系列新型MAT2a抑制剂的发现
Structure-Based Discovery of a Series of Novel MAT2a Inhibitors.
作者信息
Zhou Yushan, Wang Li, Ren Ruyue, Zhang Junjie, Huan Xiajuan, Yang Peng, Miao Ze-Hong, Xiong Bing, Wang Yingqing, Liu Tongchao
机构信息
Wuya College of Innovation, Shenyang Pharmaceutical University,103 Wenhua Road, Shenyang, Liaoning 110016, P. R. China.
Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P. R. China.
出版信息
ACS Med Chem Lett. 2025 Mar 15;16(4):646-650. doi: 10.1021/acsmedchemlett.5c00049. eCollection 2025 Apr 10.
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 in complex with the MAT2a dimer, compound was synthesized, demonstrating potent MAT2a inhibition (IC = 20 nM) and significantly enhanced antiproliferative activity (IC = 10 nM against HAP1MTAP cells). Moreover, compound exhibited improved selectivity compared to both and .
甲硫氨酸腺苷转移酶2a（MAT2a）因其在与MTAP缺陷肿瘤相关的合成致死机制中的作用，已成为一个有前景的治疗靶点。在本研究中，我们描述了通过基于片段连接策略鉴定一系列新型MAT2a抑制剂的工作，从而开发出一种占据MAT2a二聚体变构位点的单一分子。在与MAT2a二聚体复合物的共结构指导下，合成了化合物，其显示出强效的MAT2a抑制作用（IC = 20 nM）和显著增强的抗增殖活性（对HAP1MTAP细胞的IC = 10 nM）。此外，与和相比，化合物表现出更好的选择性。
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