Activity-Guided Design of HDAC11-Specific Inhibitors
Se In Son 1, Ji Cao 1, Cheng-Liang Zhu 1, Seth P Miller 1, Hening Lin 1 2

Mammalian histone deacetylases (HDACs) really are a type of enzymes that play important roles in biological pathways. Existing HDAC inhibitors target multiple HDACs with little selectivity. Inhibitors that concentrate on a particular HDAC is going to be helpful for investigating the biological functions of HDACs as well as for developing better therapeutics. Here, we report the introduction of HDAC11-specific inhibitors utilizing an activity-led rational design approach. The enzymatic activity and biological purpose of HDAC11 happen to be little-known, but recent surveys claim that it’s efficient defatty-acylation activity which inhibiting it may be helpful for the treatment of a number of human illnesses, including viral infection, ms, and metabolic illnesses. Our very best inhibitor, SIS17, is active in cells and inhibited the demyristoylation of the known HDAC11 substrate, serine hydroxymethyl transferase 2, without inhibiting other HDACs. The game-led design can also be helpful to add mass to isoform-specific inhibitors for other classes of enzymes.