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.