各种疾病与HDAC8功能异常密切相关。这些异常可以归结为HDAC8的结构功能或催化功能。因此，开发HDAC8降解诱导剂可能比HDAC8抑制剂更有前途。我们采用蛋白酶解靶向嵌合体（PROTAC）策略，开发出一种选择性和强效的HDAC8降解诱导剂CT-4，其在三阴性乳腺癌MDA-MB-231细胞和T细胞白血病细胞中具有低于10纳摩尔的DC50值和超过95％的Dmax。值得注意的是，CT-4在MDA-MB-231细胞中表现出强大的抗迁移活性和有限的抗增殖活性。相反，CT-4有效诱导Jurkat细胞的凋亡性细胞死亡，通过caspase 3/7活性测定和流式细胞术评估。我们的研究结果表明，开发HDAC8降解诱导剂在HDAC8相关疾病治疗方面具有巨大潜力。版权所有© 2023作者。由Elsevier公司出版。保留所有权利。

Various diseases are deeply associated with aberrations in HDAC8 functions. These aberrations can be assigned to either structural functions or catalytic functions of HDAC8. Therefore, development of HDAC8 degradation inducers might be more promising than HDAC8 inhibitors. We employed the proteolysis targeting chimera (PROTAC) strategy to develop a selective and potent HDAC8 degradation inducer CT-4 with single-digit nanomolar DC50 values and over 95% Dmax in both triple-negative breast cancer MDA-MB-231 cells and T-cell leukemia cells. Notably, CT-4 demonstrated potent anti-migration activity and limited anti-proliferative activity in MDA-MB-231 cells. In contrast, CT-4 effectively induced apototic cell death in Jurkat cells, as assessed by a caspase 3/7 activity assay and flow cytometry. Our findings suggest that the development of HDAC8 degradation inducers holds great potential for the treatment of HDAC8-related diseases.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.