Identification of a mechanism-based binding mode for a histone deacetylase 6 inhibitor - PubMed
5 hours ago
- #HDAC6 inhibitor
- #mechanism-based binding
- #species selectivity
- BAS-2 is a selective HDAC6 inhibitor with an isothiouronium core and lacks a zinc-binding group.
- The inhibitor shows species selectivity, potently inhibiting human HDAC6 but not zebrafish HDAC6, due to Asp567 in human HDAC6.
- X-ray crystallography and mutagenesis revealed a mechanism-based binding mode involving thiolate-zinc coordination in a variant.
- Using BAS-2's binding orientation, a proteolysis targeting chimera was designed to induce proteasome-dependent HDAC6 degradation.
- The findings provide insights for developing next-generation selective HDAC6 inhibitors and degraders.