Discovery of a Selective Histone Deacetylase 6 Degrader (HDAC6 PROTAC) with a Short and Rigid Linker Demonstrating Sustained Knockdown of HDAC6 In Vivo

Histone deacetylase 6 (HDAC6) is a cytosolic enzyme that regulates protein acetylation and contributes to the pathogenesis of various lung diseases. We report the discovery and characterization of a novel HDAC6 degrader, compound 15, designed by conjugating a selective hydroxamic acid HDAC6 inhibitor (2) to a cereblon-recruiting ligand via a short, rigid linker. Compound 15 exhibited selective HDAC6 degradation with subnanomolar degradation potency in bronchial epithelium cells, effectively inducing α-tubulin hyperacetylation without affecting histone-3 acetylation. In mice, subcutaneous administration achieved high bioavailability (65%) and sustained HDAC6 knockdown in lung tissue for up to 96 h after a single dose, repeated dosing further enhanced degradation and α-tubulin acetylation. Safety and secondary pharmacology profiling confirmed a favorable preclinical safety and selectivity profile. These findings established compound 15 as a potent, selective HDAC6 degrader suitable as a starting point and tool for studying HDAC6-related diseases in the lung epithelium and beyond.