Discovery of Novel MTA-Cooperative PRMT5 Inhibitors with a 2,3-Dihydro‑1H‑imidazo[1,2‑b]pyrazole Scaffold.

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-06-27 eCollection Date: 2025-07-10 DOI:10.1021/acsmedchemlett.5c00185

Yuxin Yang, Zonglong Chen, Yujie Wang, Xun Huang, Chun Hu, Hong Yang, Yingxia Li

引用次数: 0

Abstract

Protein arginine methyltransferase 5 (PRMT5) has recently emerged as a synthetically lethal target in methylthioadenosine phosphorylase (MTAP)-deficient tumors due to the formation of the PRMT5·MTA complex. Herein we report a series of novel PRMT5·MTA inhibitors bearing a 2,3-dihydro-1H-imidazo-[1,2-b]-pyrazole scaffold by structure-based drug design. Among these, compound 31 exhibits potent inhibitory activity against PRMT5·MTA (IC₅₀ = 6.6 nM) with 339-fold selectivity against PRMT5 while selectively inhibiting cell growth in MTAP-deleted HCT-116 cells (IC₅₀ = 319 nM) compared to MTAP-wild-type cells. These results make compound 31 a promising lead compound for further optimization.

查看原文本刊更多论文

具有2,3-二氢- 1H -咪唑[1,2 - b]吡唑支架的新型mta协同PRMT5抑制剂的发现。

由于PRMT5·MTA复合物的形成，蛋白精氨酸甲基转移酶5 （PRMT5）最近成为甲基硫腺苷磷酸化酶（MTAP）缺陷肿瘤的合成致死靶点。在此，我们通过基于结构的药物设计报道了一系列新型PRMT5·MTA抑制剂，它们含有2,3-二氢- 1h -咪唑-[1,2-b]-吡唑支架。其中，化合物31对PRMT5·MTA具有较强的抑制活性（IC50 = 6.6 nM），对PRMT5具有339倍的选择性，而在mtap缺失的HCT-116细胞（IC50 = 319 nM）中，与mtap野生型细胞相比，化合物31对细胞生长具有选择性抑制作用。这些结果使化合物31成为一个有希望进一步优化的先导化合物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

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.