Discovery of an HDAC2-Selective Inhibitor via Enzyme−Inhibitor-Binding Thermodynamics/Kinetics as a Prospective Neurological Disorder Drug

In this study, we identified KTT-1 (12) as an HDAC2-selective inhibitor through in vitro evaluations based on both thermodynamics and kinetics of the enzyme-inhibitor binding. This approach stands in sharp contrast to conventional drug discovery research, which usually focuses only on thermodynamics. An X-ray crystallography study on HDAC2 complexed with 12 in combination with quantum chemical calculations on model compounds suggested that the 2-furanyl group of 12 contributes to the selective HDAC2 inhibition. In our cellular assays, 12 preferentially inhibited HDAC2 over its highly homologous HDAC1 and promoted neurite outgrowth of neuro-2a cells. Furthermore, treatment of mice with 12 improved the memory and depression-like behavior of stress-vulnerable mice. The results indicate that 12 is a promising lead compound for neurological disorders such as Alzheimer's disease and depression and demonstrate that inhibitor evaluations that combine enzyme-inhibitor-binding thermodynamics and kinetics are useful tools for drug discovery research.