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基于结构的识别新型素脱乙酶4 (HDAC4) 抑制剂

Rupesh Agarwal^1,2, Pawat Pattarawat³, Michael R Duff²

¹UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, TN 37830, USA.

Pharmaceuticals (Basel, Switzerland)

|July 27, 2024

概括

研究人员使用分子建模识别了癌症标HDAC4上的新口袋. 这导致发现了选择性抑制HDAC4的化合物,为癌症药物开发提供了新的策略.

科学领域:

生物化学生物化学
分子生物学分子生物学
药用化学医学化学

背景情况:

基因组脱乙酶 (HDACs) 是癌症治疗中的关键点.
目前FDA批准的HDAC抑制剂由于在HDAC类中保留了催化口袋,缺乏特异性.
针对特定类别的口袋对于开发更精确的癌症药物至关重要.

研究的目的:

识别和准IIa类HDAC中的新型,类特定的口袋,重点关注HDAC4.4.
发现与这些独特的口袋结合的小分子,与现有的抑制剂相比,提供了不同的作用机制.
评估已识别的化合物对HDAC4和其他HDAC的选择性和有效性,以及在癌症细胞系中.

主要方法:

利用分子建模和集体对接来选针对 HDAC4.4 中潜在的全囊向化合物的化合物.
员工共识评分,以优先考虑潜在的药物候选者.
进行了实验性结合试验,以比较化合物活性与HDAC4和HDAC3.
评估了活性化合物的有效性在人类乳腺和尿癌细胞系中.

主要成果:

在HDAC4-NCoR接口上发现了特定于HDAC4的新型口袋.
化合物88402可以选择性地抑制HDAC4,但不能抑制HDAC3.
化合物67436和134199显示HDAC4的微分子IC50值较低,与SAHA相似,但对HDAC3显著较弱,表明选择性有限.
五种化合物对人类乳腺癌和/或尿癌细胞系表现出活性.

结论:

该研究提出了一种开发选择性HDAC4抑制剂的新策略,通过针对特定类别的口袋来开发选择性HDAC4抑制剂.
已识别的化合物为开发下一代HDAC向癌症治疗提供了化学基础.
这种方法可以通过提高药物特异性,导致更有效,更少的毒性癌症治疗.

关键词:

计算机辅助药物设计 (CADD)组合对接对接方式在 HDAC4 中,HDAC4 是希斯脱乙酶抑制剂 (HDACi) 的使用基因组脱乙酶 (HDACs) 是一种分子动力学模拟 (MDS) 模型基于结构的药物发现 (SBDD)

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