由于 I 类 HDAC 在表观遗传修饰中的作用，它们被认为是有希望的癌症靶标。开发新型、有效且无毒的 I 类 HDAC 抑制剂的主要挑战是选择性和适当的药代动力学。 PROTAC 技术（蛋白水解靶向嵌合体）是药物开发中的一种新方法，用于生产可以降解而不是抑制目标蛋白 (POI) 的活性物质。这项技术将开启生产具有高安全边际的选择性强效药物的时代。之前，我们报道了针对用氨基苯甲酰胺或异羟肟酸基团功能化的 I 类 HDAC 的不同抑制剂。在目前的研究工作中，我们将在之前报道的抑制剂的基础上，采用PROTAC技术来开发I类HDAC降解剂。我们合成了两个系列的基于氨基苯甲酰胺的 PROTAC 和基于异羟肟酸酯的 PROTAC，并在体外针对 I 类 HDAC 进行了测试。为了确保它们的降解，所有这些都针对 HDAC2 作为 I 类的代表性例子进行了筛选。最佳候选者在各种 HDAC 亚型的不同浓度下进行了评估。由此产生的 PROTAC (32a) (HI31.1) 可降解 HDAC8，DC50 为 8.9 nM，并且对其他同工酶具有适当的选择性。此外，PROTAC 32a 能够以 DC50 = 14.3 nM 降解 HDAC6。对白血病细胞 (MV-4-11) 的细胞凋亡研究显示，100 nM 时超过 50% 发生细胞凋亡。 PROTAC 32a (HI31.1) 对正常细胞系表现出良好的安全边际和适当的化学稳定性。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

Class I HDACs are considered promising targets for cancer due to their role in epigenetic modifications. The main challenges in developing a new, potent and non-toxic class I HDAC inhibitor are selectivity and appropriate pharmacokinetics. The PROTAC technique (Proteolysis Targeting Chimera) is a new method in drug development for the production of active substances that can degrade a protein of interest (POI) instead of inhibiting it. This technique will open the era to produce selective and potent drugs with a high margin of safety. Previously, we reported different inhibitors targeting class I HDACs functionalized with aminobenzamide or hydroxamate groups. In the current research work, we will employ PROTAC technique to develop class I HDAC degraders based on our previously reported inhibitors. We synthesized two series of aminobenzamide-based PROTACs and hydroxamate-based PROTACs and tested them in vitro against class I HDACs. To ensure their degradation, all of them were screened against HDAC2 as representative example of class I. The best candidates were evaluated at different concentrations at various HDAC subtypes. This resulted in the PROTAC (32a) (HI31.1) that degrades HDAC8 with a DC50 of 8.9 nM with a proper margin of selectivity against other isozymes. Moreover, PROTAC 32a is able to degrade HDAC6 with DC50 = 14.3 nM. Apoptotic study on leukemic cells (MV-4-11) displayed more than 50 % apoptosis took place at 100 nM. PROTAC 32a (HI31.1) showed a good margin of safety against normal cell line and proper chemical stability.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.