Discovery of a Highly Potent and Selective HDAC3 and HDAC8 PROTAC Dual Degrader

HDAC3 and HDAC8 are members of class I deacetylases involved in several biological mechanisms and represent a highly sought-after therapeutic target for drug development. It is historically challenging to develop selective deacetylase inhibitors due to their conserved catalytic domains. HDAC3 also has deacetylase-independent activity, which cannot be blocked by conventional enzymatic inhibitors. Recent advance in proteolysis-targeting chimeras (PROTACs) provides an opportunity to eliminate the whole protein selectively, 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 and HDAC8 without trigging pan-HDAC inhibitory effects. Unbiased quantitative proteomics experiments further confirmed its high selectivity. This dual-specific degrader specifically ablates cellular pathways attributed to HDAC3 and HDAC8 and exhibits high potency in killing cancer cells. YX968 represents a new probe for dissecting the complex biological functions of HDAC3 and HDAC8. MDA-MB-231 cells were cultured in 6-well plate and treated with DMSO, 3, or 30 nM of YX968 for 14 h. Total RNAs were isolated using the RNeasy mini kit (Qiagen). Total RNAs were used for RNA-seq Poly A library constructions and sequencing was done with 20M raw reads/sample using the Illumina NovaSeq 6000 S4 2x150 platform at the Interdisciplinary Center for Biotechnology Research, University of Florida.