Discovery of a Highly Potent and Selective HDAC3 and HDAC8 PROTAC Dual Degrader
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ABSTRACT: 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 advances in proteolysis-targeting chimeras (PROTACs) provide an opportunity to eliminate the whole protein selectively, abolishing both enzymatic and scaffolding functions. 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.
INSTRUMENT(S): Orbitrap Eclipse
ORGANISM(S): Homo Sapiens (ncbitaxon:9606)
SUBMITTER: Yufeng Xiao
PROVIDER: MSV000091511 | MassIVE | Mon Mar 20 09:08:00 GMT 2023
SECONDARY ACCESSION(S): PXD040980
REPOSITORIES: MassIVE
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