基于结构的一系列新型MAT2a抑制剂的发现。

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-03-15 eCollection Date: 2025-04-10 DOI:10.1021/acsmedchemlett.5c00049

Yushan Zhou, Li Wang, Ruyue Ren, Junjie Zhang, Xiajuan Huan, Peng Yang, Ze-Hong Miao, Bing Xiong, Yingqing Wang, Tongchao Liu

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引用次数: 0

摘要

蛋氨酸腺苷转移酶2a （Methionine adenosyltransferase 2a, MAT2a）已成为一个有希望的治疗靶点，因为它在与mtap缺陷肿瘤相关的合成致死性机制中发挥作用。在这项研究中，我们描述了我们通过基于片段的连接策略鉴定一系列新的MAT2a抑制剂的努力，从而开发了一个占据MAT2a二聚体变弹性位点的单分子。利用AZ-28与MAT2a二聚体配合物的结构，合成了化合物9，对MAT2a具有较强的抑制作用（IC50 = 20 nM），对HAP1MTAP-/-细胞的抗增殖活性显著增强（IC50 = 10 nM）。此外，与AZ-28和AG-270相比，化合物9具有更高的选择性。

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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 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.

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.