Dual CDK6 and CDK9 inhibitors as anti-psoriasis agents: Design, synthesis, and anti-inflammatory activity

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-06-21 DOI:10.1016/j.bmcl.2025.130316

Yiming Ru , Fang Zhao , Haojie Zuo , Xiuxiu Gao , Yaoyao Yan , Xiaodong Ma , Yang Wang

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Abstract

Skin hyperplasia and aberrant secretion of inflammatory factors are typical features of psoriasis. Given the cooperative role of CDK6-mediated cell proliferation and CDK9-mediated disturbance of inflammatory cytokines in the progression of psoriasis, dual inhibition of CDK6 and CDK9 is expected to not only exert synergetic anti-psoriatic effects but also reduce the toxicity of single-target inhibition. In this study, on the basis of our previously discovered lead, a total of 17 final compounds were designed and synthesized for exploring additional hydrogen bond interactions with hydrophilic residues in the inner pocket of CDK6 or CDK9. Among them, 4, with dual CDK6 and CDK9 inhibitory activities, was capable to ameliorate inflammation in vitro. Furthermore, it inhibited the activation of STAT3 pathway and decreased the mRNA levels of inflammatory factors in IFN-γ/TNF-α-induced HaCaT cells. These findings indicate dual CDK6 and CDK9 inhibitors may emerge as potential therapeutic agents for psoriasis.

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双CDK6和CDK9抑制剂作为抗牛皮癣药物：设计、合成和抗炎活性

皮肤增生和炎性因子的异常分泌是银屑病的典型特征。考虑到CDK6介导的细胞增殖和CDK9介导的炎症因子干扰在银屑病进展中的协同作用，CDK6和CDK9的双重抑制不仅可以发挥协同抗银屑病作用，还可以降低单靶点抑制的毒性。在本研究中，在我们之前发现的铅的基础上，共设计和合成了17个最终化合物，用于探索CDK6或CDK9内袋中亲水残基的额外氢键相互作用。其中4种具有CDK6和CDK9双抑制活性，能够在体外改善炎症。抑制STAT3通路的激活，降低IFN-γ/TNF-α-诱导的HaCaT细胞中炎症因子mRNA水平。这些发现表明CDK6和CDK9双抑制剂可能成为银屑病的潜在治疗药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.