Binding kinetics help isolate HDAC2-selective inhibitor KTT-1
- KTT-1 (compound 12) was identified as HDAC2-selective by evaluating both thermodynamics and kinetics of enzyme–inhibitor binding, rather than affinity alone.
- Crystallography of HDAC2 with the compound, plus quantum chemical calculations on model compounds, suggests its 2-furanyl group drives the selectivity.
- In cells it preferentially inhibited HDAC2 over the highly homologous HDAC1 and promoted neurite outgrowth; in stress-vulnerable mice it improved memory and depression-like behavior.
💡 Points
Screening on residence time rather than IC50 alone is how you get past the near-identical HDAC1/2 active sites, and a furanyl contact backed by both crystallography and QM is a clean, testable rationale. Cellular HDAC2-over-HDAC1 preference is rare, so I'd want it confirmed in neurons with real brain exposure.