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在希斯脱乙酶 (HDAC) 抑制剂中探索替代结合组揭示了DS-103作为一种具有化学敏感性质的基于乙基的强大的HDAC抑制剂

Daniel Stopper¹, Lukas Biermann², Paris R Watson³

¹Department of Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, 53121 Bonn, Germany.

Journal of medicinal chemistry

|February 13, 2025

概括

一种新的基于peptoid的化合物,DS-103,有效地抑制了基因素脱乙酶 (HDAC) 酶,并逆转了癌细胞中西斯普拉丁的耐药性. 这种新型HDAC抑制剂通过增强DNA损伤和亡,显示出对协同癌症治疗的前景.

科学领域:

药用化学医学化学
癌症生物学癌症生物学
结构生物学结构生物学

背景情况:

基斯脱乙酶 (HDAC) 抑制剂在癌症治疗中至关重要.
开发具有提高疗效和逆转耐药性质的新型HDAC抑制剂至关重要.
了解HDAC抑制剂的结合机制有助于药物设计.

研究的目的:

为了合成和评估新的基于peptoid的HDAC抑制剂.
为了研究合成化合物的抗等离子体活性和细胞毒性.
为了阐明化合物DS-103与HDAC6.6的结合方式.

主要方法:

合成具有多种链接区域和结合群的基于类化合物.
在体外测定HDAC抑制,抗等离子体活性和细胞毒性.
进行X射线晶体学以确定DS-103与HDAC6.6复合体中的结构.

主要成果:

DS-103证明了强大的纳米分子抑制I类HDACs和HDAC6.
具有HDAC6的DS-103的晶体结构为其结合模式提供了洞察力.
在抗的癌症细胞系中,DS-103逆转了对的抗性,并与显示出协同作用.
协同效应涉及增加的DNA损伤,p21表达和卡斯巴酶介导的亡.

结论:

DS-103是一种高效的基于peptoid的HDAC抑制剂,在癌症治疗中具有显著的潜力.
DS-103克服了西斯普拉丁耐药性,并与西斯普拉丁表现出协同效应.
DS-103-HDAC6复合物的结构洞察力可以指导HDAC抑制剂的未来药物开发.

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