Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Medicinal Chemistry, School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Medicinal Chemistry, School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
Life Sci. 2022 Nov 1;308:120946. doi: 10.1016/j.lfs.2022.120946. Epub 2022 Sep 10.
Histone deacetylases (HDACs) are one of the essential epigenetic targets in cancer treatment. These enzymes play key roles in post-translation modification (PTM) and gene expression, and consequently, their inhibitors are about to find their place in pharmacotherapy. Most of the currently approved HDAC inhibitors (HDACIs) are wide-spectrum with poor clinical outcomes and numerous side effects. Therefore, new generations of HDAC-based chemotherapeutics with better clinical outcomes are emerging, e.g., isoform-selective inhibitors, multitargeted HDACIs, as well as HDAC degraders.
The review intended to introduce drug design approaches which were used for designing novel agents which can be beneficial in the process of finding new and more effective HDACI-based therapeutics.
PubMed and other databases were searched for literature regarding the structure-function of HDAC isoforms, and strategies used to design HDAC inhibitors. Also, all clinical trials available from the ClinicalTrials site for years 2021-2022 were investigated.
It is expected that the future of drug discovery projects in HDAC field will concentrate mostly on issues such as isoform-selectivity, multitargeted HDAC inhibitors and HDAC degraders. Deeper knowledge of the 3D structure of HDACs complexed with inhibitors and extensive delineation of biological roles of HDACs are needed for efficient investigations leading to the discovery of novel potent inhibitors.
Histone deacetylases (HDACs) are one of the important epigenetic targets in cancer treatment drug discovery. Comprehending the structure of HDAC isoforms along with applied drug design strategies can inspire new ideas.
组蛋白去乙酰化酶（HDACs）是癌症治疗中重要的表观遗传学靶点之一。这些酶在翻译后修饰（PTM）和基因表达中发挥关键作用，因此，它们的抑制剂即将在药物治疗中找到自己的位置。目前批准的大多数 HDAC 抑制剂（HDACIs）都是广谱的，临床效果不佳，副作用众多。因此，出现了新一代基于 HDAC 的化疗药物，具有更好的临床效果，例如，同工酶选择性抑制剂、多靶点 HDACIs 以及 HDAC 降解剂。
本综述旨在介绍用于设计新型药物的药物设计方法，这些新型药物可能有助于寻找新的、更有效的基于 HDACI 的治疗方法。
在 PubMed 和其他数据库中搜索有关 HDAC 同工酶的结构-功能以及设计 HDAC 抑制剂的策略的文献。还调查了 ClinicalTrials 网站上 2021-2022 年所有的临床试验。
预计 HDAC 领域药物发现项目的未来将主要集中在同工酶选择性、多靶点 HDACIs 和 HDAC 降解剂等问题上。需要更深入地了解与抑制剂结合的 HDAC 的 3D 结构以及广泛阐明 HDAC 的生物学作用，以便进行有效的研究，从而发现新型有效抑制剂。
组蛋白去乙酰化酶（HDACs）是癌症治疗药物发现中重要的表观遗传学靶点之一。了解 HDAC 同工酶的结构以及应用的药物设计策略可以激发新的思路。
