Targeted protein degradation refers to the use of small molecules that recruit a ubiquitin ligase to a target protein for ubiquitination and subsequent proteasome-dependent degradation. While degraders have been developed for many targets, key questions regarding degrader development and the consequences of acute pharmacological degradation remain, specifically for targets that exist in obligate multi-protein complexes. Here, we synthesize a pan-histone deacetylase (HDAC) degrader library for the chemo-proteomic exploration of acute degradation of a key class of chromatin-modifying enzymes. Using chemo-proteomics, we not only map the degradability of the zinc-dependent HDAC family identifying leads for targeting HDACs 1–8 and 10 but also explore important aspects of degrading epigenetic enzymes. We discover cell line-driven target specificity and that HDAC degradation often results in collateral loss of HDAC-containing repressive complexes. These findings potentially offer a new mechanism toward controlling chromatin structure, and our resource will facilitate accelerated degrader design and development for HDACs.

靶向蛋白质降解是指使用小分子将泛素连接酶招募到靶蛋白上，进行泛素化和随后的蛋白酶体依赖性降解。虽然已经针对许多靶标开发了降解剂，但有关降解剂开发和急性药理降解后果的关键问题仍然存在，特别是对于专性多蛋白复合物中存在的靶标。在这里，我们合成了一个泛组蛋白脱乙酰酶（HDAC）降解剂库，用于对一类关键染色质修饰酶的急性降解进行化学蛋白质组学探索。利用化学蛋白质组学，我们不仅绘制了锌依赖性 HDAC 家族的降解性图谱，确定了针对 HDAC 1-8 和 10 的先导化合物，而且还探索了降解表观遗传酶的重要方面。我们发现细胞系驱动的靶标特异性，并且 HDAC 降解通常会导致含有 HDAC 的抑制复合物的附带损失。这些发现可能提供一种控制染色质结构的新机制，我们的资源将促进加速 HDAC 降解剂的设计和开发。