Improved Pharmacokinetic Profiles of HDAC6 Inhibitors via Cap Group Modifications.

Hydroxamic acid (HA)-based HDAC inhibitors often suffer from poor pharmacokinetic (PK) profiles, limiting their in vivo applications. Cap group modification offers a promising strategy to address these challenges. Here, we optimized the cap group of TO-317, a selective HDAC6 inhibitor with a bisected cap structure, generating 26 analogs with comparable or improved HDAC6 binding affinity and selectivity. Replacing the redundant tetrafluorobenzene sulfonamide cap while retaining the essential picolyl cap group preserved the critical H614 hydrogen bond, as confirmed by X-ray crystallography (1.24-1.27 Å resolution) of five analogs. Analog 14, featuring a 2-chlorobenzene sulfonamide cap, demonstrated a 120-fold enhancement in plasma concentration in mice compared to that of TO-317. Preclinical studies showed that analog 14 achieved 56% tumor growth inhibition in an SM1 melanoma murine model without observed toxicity. These findings highlight cap group optimization as a powerful approach to enhance HA-based HDAC inhibitors for advanced preclinical and clinical development.