Structure-based identification of novel histone deacetylase 4 (HDAC4) inhibitors

AbstractHistone deacetylases (HDACs) are important cancer drug targets. Existing FDA-approved drugs target the catalytic pocket of HDACs, which is conserved across subfamilies (classes) of HDAC. Here, we use molecular modeling approaches to identify and target potential novel pockets specific to Class IIA HDAC-HDAC4 at the interface between HDAC4 and the NCOR protein. These pockets were then targeted using an ensemble docking approach combined with consensus scoring to identify compounds with a different mechanism of binding than the currently known HDAC modulators. Using this approach, 18 compounds predicted in silico to bind to HDAC4’s novel pockets were tested 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). While there are currently no known inhibitors reported to bind highly selectively to HDAC4, the present result suggests potential mechanistic and chemical approaches for the development of selective HDAC4 modulators.