磺胺衍生物作为有效CDK9抑制剂的设计、合成和生物学评价

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-08-26 DOI:10.1021/acsmedchemlett.5c00430

Yifang Liu, Zexu Wang, Yifan Xu, Liyan Yang, Xiaolei Yang, Zhiyu Li, Jinlei Bian, Jubo Wang*, Lixia Pan* and Tizhi Wu*,

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引用次数: 0

摘要

靶向CDK9已成为一种有吸引力的抗肿瘤药物开发策略。为了获得高活性、高安全性的CDK9抑制剂，我们以首个进入临床试验的选择性CDK9抑制剂BAY1143572为基础，设计合成了一系列磺胺类衍生物作为CDK9抑制剂。其中，代表性化合物L18被鉴定为一种有效的选择性CDK9抑制剂（IC50 = 3.8 nM）。生物学评价显示，L18通过下调MV4-11细胞中Myc-1和c-Myc的水平，显著抑制多种肿瘤细胞的生长，诱导凋亡。进一步的研究表明，L18具有中等代谢特性，其体内安全性优于阳性对照。这项研究为开发用于癌症治疗的CDK9抑制剂提供了一个潜在的先导化合物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Design, Synthesis, and Biological Evaluation of Sulfonamide Derivatives as Potent CDK9 Inhibitors

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Design, Synthesis, and Biological Evaluation of Sulfonamide Derivatives as Potent CDK9 Inhibitors

Targeting CDK9 has become an attractive strategy for antitumor drug development. To obtain CDK9 inhibitors with high activity and safety, we designed and synthesized a series of sulfonamide derivatives as CDK9 inhibitors based on BAY1143572, the first selective CDK9 inhibitor to enter clinical trials. Among them, the representative compound L18 was identified as a potent and selective CDK9 inhibitor (IC₅₀ = 3.8 nM). Biological evaluation showed that L18 significantly inhibited the growth of various tumor cells and induced apoptosis by down-regulating the levels of Myc-1 and c-Myc in MV4-11 cells. Further studies showed that L18 possessed moderate metabolic properties and exhibited an in vivo safety profile superior to that of the positive control. This study provides a potential lead compound for the development of CDK9 inhibitors for cancer therapy.

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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.