Development ofHydrophobic Tag Based HDAC6 Degraderfor Ulcerative Colitis Treatment

Abstract Targeted protein degradation via hydrophobic tagging technology presents a promising strategy for modulating disease relevant proteins. As a unique member of the histone deacetylase (HDAC) family, HDAC6 is involved in inflammatory pathways and is a potential therapeutic target for inflammatory diseases. Herein, we report a group of novel hydrophobic tag based HDAC6 degraders by modifying the structure of Nexturastat A and identified 20c as a lead compound which selectively degrades HDAC6 in vitro (half-degradation concentration = 1.1 μM) in a ubiquitin-proteasome system dependent manner without obviously impacting six other HDAC isoforms. In a dextran sulfate sodium (DSS)-induced colitis model, 20c alleviated disease symptoms, reduced colon shortening, and downregulated pro-inflammatory cytokines. Transcriptomic and biochemical analyses revealed that 20c suppresses NF-κB signaling through the HDAC6–HSP90–NF-κB axis. Overall, this work validated the potential of hydrophobic tag based HDAC6 degrader as therapeutic means for ulcerative colitis.