Modulators of Class IIa HDACs

About

BACKGROUND Histone deacetylases (HDACs) are enzymes that mediate the removal of acetyl groups from numerous acetylated proteins (including histones) and some are associated with the cell cycle, inflammation, apoptosis and cancer. HDACs have been found to be involved in a wide range of diseases and conditions and represent promising drug targets. There are eleven zinc-binding mammalian HDACs including 4 class I, 4 class IIa and 2 class IIb proteins. These HDACs have a tubular active site, but their structural similarity makes it difficult to develop specific ligands for each HDAC. Belinostat, panobinostat, romidepsin are among approved anti-cancer drugs that indiscriminately inhibit multiple HDACs (Classes I, IIa, IIb). Whilst Class I HDACs are ubiquitous in human tissues and control chromatin condensation in the cell nucleus, Class IIa HDACs have more restricted tissue expression and do not deacetylate histones in the nucleus [1,2]. Selective binding to Class IIa HDACs over Class I HDACs has the potential to be more tissue specific with fewer side effects. THE TECHNOLOGY The Fairlie Research Group at The University of Queensland (UQ) has exploited structural differences between Class I and IIa HDACs to develop two generations of new compounds that are potent and selective inhibitors of class IIa HDACs. More than 80 second generation inhibitors have been made and evaluated in their lab in enzyme, cell and rodent studies, with IC50 ~10nM in vitro against class IIa HDAC enzymes. The compounds show selectivity (~100-10,000-fold) for Class IIa (e.g. HDAC7, HDAC4) over Class I (e.g. HDAC1) or Class IIb (e.g. HDAC6). Other in vitro data includes cellular assays showing: selective inhibition of processing for substrates of class IIa but not class I HDACs; no inhibitor-induced hyperacetylation of histone H4 in cells, unlike most HDAC inhibitors; inhibition of inflammatory cytokines secreted from macrophages stimulated by LPS. DEVELOPMENT STAGE The UQ research group has demonstrated stability in rat liver microsomes, and anti-inflammatory activity and blood-brain permeability in rodents. For example, in a 20-day rat model of collagen-induced arthritis (CIA), involving collagen II immunisation on days 0 and 7, an inhibitor LL87 (10 mg/kg s.c., days 7-19) of class II HDACs reduced hind paw swelling, slowed disease progression and reduced structural damage of the ankle joint and collagen loss in the joint cartilage. LL87 also resulted in a reduction of joint macrophages, osteoclasts, inflammatory cytokines and other markers of arthritis.