HDAC6 as privileged target in drug discovery: A perspective

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• HDAC6, a class IIB HDAC, uniquely targets non-histone proteins beyond histones.
• Its cytoplasmic localization influences diverse physiological and pathological processes.
• HDAC6 is implicated in neurological disorders, cancers, rare diseases, and immunological conditions.

Purpose of the Study:

• To review the structural biology of HDAC6.
• To elucidate the physiological and pathological roles of HDAC6 in disease.
• To analyze structure-activity relationships (SARs) of known HDAC6 inhibitors (HDAC6is).

Main Methods:

• Literature review focusing on HDAC6 structural biology.
• Analysis of HDAC6's role in various signaling pathways and disease states.
• Examination of SARs for existing HDAC6is, including pharmacophore features.

Main Results:

• HDAC6 regulates non-histone proteins like Hsp90, α-tubulin, and cortactin.
• Targeting HDAC6 shows therapeutic potential across multiple disease areas.
• Current HDAC6is, like ACY-1215 and ACY-241, are in clinical trials, but selectivity remains a challenge.

Conclusions:

• Understanding HDAC6 structure and function is key to developing targeted therapies.
• Modifying the cap group of HDAC6is can enhance inhibitor selectivity.
• This review provides insights for designing novel, potent, and selective HDAC6 inhibitors.