Structure-based discovery of selective histone deacetylase (HDAC) 3 and 4 inhibitors

Histone deacetylases (HDACs) are a family of proteins that are very important cancer drug targets. Several FDA-approved drugs target the conserved catalytic pocket of HDACs and thus lack selectivity for subfamilies (classes) of HDAC. In this study, we aimed to target HDAC4 from Class IIA, which is linked to various common cancers. There are no known inhibitors reported to bind specifically to HDAC4. Using classical and accelerated molecular dynamics (MD) simulations, we identified novel pockets in the interface between HDAC4 and the protein NCOR, which are not observed in the available crystal structures. These pockets were then targeted using an ensemble docking approach combined with consensus scoring. Using this approach, we selected 18 compounds for in vivo testing on two cancer cell lines. Of these, 5 compounds decreased cell viability to less than 60%. One inhibited the catalytic activity of HDAC4 but not HDAC3, which belongs to a different family of HDACs (Class I). The most potent compound has an IC50 comparable to the FDA-approved compound SAHA (Vorinostat). Targeting pockets other than the active site is thus a viable strategy for developing selective HDAC inhibitors. ### Competing Interest Statement The authors have declared no competing interest.