HDAC3和HDAC8具有重要的生物功能，并且是备受追捧的治疗靶点。由于组蛋白去乙酰化酶（HDAC）具有非常保守的催化结构域，开发特异性同工酶抑制剂仍然具有挑战性。HDAC3/8还具有非去乙酰化酶依赖的活性，传统的酶抑制剂无法阻断该活性。蛋白酶降解-靶向嵌合体（PROTAC）可以选择性降解目标酶，同时废除其酶活性和骨架功能。在本研究中，我们报道了一种新型HDAC3/8双降解剂YX968，可以高效、迅速、选择性地降解HDAC3/8，而不触发全HDAC抑制效应。无偏向的定量蛋白质组学实验证实了其高选择性。YX968对HDAC3/8的降解不会引起组蛋白高乙酸化和广泛的转录组扰乱。因此，组蛋白高乙酸化可能是改变转录的主要因素。YX968在体外促进细胞凋亡，并具有高效的抗癌细胞杀伤作用。因此，YX968成为解剖HDAC3/8复杂生物功能的新探针。版权所有© 2023 Elsevier Ltd. 保留所有权利。

HDAC3 and HDAC8 have critical biological functions and represent highly sought-after therapeutic targets. Because histone deacetylases (HDACs) have a very conserved catalytic domain, developing isozyme-selective inhibitors remains challenging. HDAC3/8 also have deacetylase-independent activity, which cannot be blocked by conventional enzymatic inhibitors. Proteolysis-targeting chimeras (PROTACs) can selectively degrade a target enzyme, abolishing both enzymatic and scaffolding function. Here, we report a novel HDAC3/8 dual degrader YX968 that induces highly potent, rapid, and selective degradation of both HDAC3/8 without triggering pan-HDAC inhibitory effects. Unbiased quantitative proteomic experiments confirmed its high selectivity. HDAC3/8 degradation by YX968 does not induce histone hyperacetylation and broad transcriptomic perturbation. Thus, histone hyperacetylation may be a major factor for altering transcription. YX968 promotes apoptosis and kills cancer cells with a high potency in vitro. YX968 thus represents a new probe for dissecting the complex biological functions of HDAC3/8.Copyright © 2023 Elsevier Ltd. All rights reserved.