Chemo-proteomics exploration of HDAC degradability by small molecule degraders

Targeted protein degradation refers to the use of small molecule protein-protein dimerizers that recruit a ubiquitin E3 ligase to a protein of interest for chemically induced degradation. Here we combine systematic exploration of 51 degraders designed to broadly target the HDAC family of proteins with chemo-proteomics, to map the degradability of zinc-dependent HDAC proteins. Our dataset provides chemical leads for targeting HDACs 1-8 and 10, and investigates important aspects of degrader design such as recruited ligase and linker length and position, to assist chemical design prioritization. We discover that targeting HDACs often results in collateral degradation of the multi-protein complexes that HDACs belong to, offering a new mechanism of controlling chromatin structure. This database is an open source resource for facilitating accelerated degrader design and development for this epigenetic class of enzymes.