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.

HDAC3 和 HDAC8 具有关键的生物学功能，是备受追捧的治疗靶点。由于组蛋白脱乙酰酶 （HDAC） 具有非常保守的催化结构域，因此开发同工酶选择性抑制剂仍然具有挑战性。HDAC3/8 还具有脱乙酰酶非依赖性活性，这是常规酶抑制剂无法阻断的。蛋白水解靶向嵌合体 （PROTAC） 可以选择性地降解靶酶，从而消除酶和支架功能。在这里，我们报道了一种新型 HDAC3/8 双重降解剂 YX968，它诱导两种 HDAC3/8 的高效、快速和选择性降解，而不会触发泛 HDAC 抑制作用。无偏倚的定量蛋白质组学实验证实了其高选择性。YX968 降解 HDAC3/8 不会诱导组蛋白高乙酰化和广泛的转录组扰动。因此，组蛋白高乙酰化可能是改变转录的主要因素。YX968 促进细胞凋亡并杀死癌细胞，在 体外具有高效效力。因此，YX968 代表了一种用于剖析 HDAC3/8 复杂生物学功能的新探针。