Download MendeleyMechanism-Based Inhibition of Histone Deacetylase 6 by a Selenocyanate Is Subject to Redox Modulation.
Goulart Stollmaier, J., Czarnecki, B.A.R., Christianson, D.W.(2025) J Am Chem Soc 147: 6373-6377
- PubMed: 39957581
- DOI: https://doi.org/10.1021/jacs.5c00157
- Primary Citation of Related Structures:
9MQP - PubMed Abstract:
Organoselenocyanates have attracted considerable attention in recent years due to their therapeutic potential and versatility in medicinal chemistry. Here, we report on the mechanism of inhibition by 5-phenylcarbamoylpentyl selenocyanide (SelSA-2), an analogue of the well-characterized histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA, a.k.a. Vorinostat). We show that histone deacetylases 6 and 10 promote selenocyanate hydrolysis to generate a selenolate anion, and we explore the redox chemistry of selenium as it modulates inhibitory activity through reversible formation of the diselenide. The 2.15 Å-resolution crystal structure of histone deacetylase 6 cocrystallized with SelSA-2 conclusively demonstrates that it is not the selenocyanate, but instead a zinc-bound selenolate anion, that is the active pharmacophore responsible for enzyme inhibition.
Organizational Affiliation:
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States.
