Identification of a mechanism-based binding mode for a histone deacetylase 6 inhibitor

作者：Daniel A. Rodrigues, Yu Wang, Juana Goulart Stollmaier, Graeme P. Sullivan, Cian D'Arcy, Aisling Y. Coughlan, Andrew Roe, Linda Bíró, P. R. Watson, J.D. Osko, Brendan Twamley, Kieran Wynne, Gerard Cagney, Péter Buglyó, Yanli Liu, Darren M. Griffith, David W. Christianson, Tríona Ní Chonghaile · 发表于：Nature Communications · 年份：2026 · DOI：10.1038/s41467-026-73146-5 · 被引用次数：1 · 研究领域：Histone Deacetylase Inhibitors Research、Ubiquitin and proteasome pathways、Sirtuins and Resveratrol in Medicine

Histone deacetylase 6 (HDAC6) is a cytoplasmic enzyme that deacetylates non-histone substrates such as α-tubulin and cortactin. HDAC6 contains two catalytic domains, each containing a catalytic zinc ion, and a zinc-finger ubiquitin-binding domain. We have discovered BAS-2, a selective HDAC6 inhibitor with an isothiouronium core and no obvious zinc-binding group. To define its mechanism, we combine X-ray crystallography, structure-activity-relationships, molecular modeling and mutagenesis. BAS-2 potently inhibits human HDAC6 but it does not inhibit zebrafish HDAC6. Computational modeling highlighted Asp567 in human HDAC6 as critical for BAS-2 recognition and mutational analyses confirmed this. The corresponding zebrafish residue is Asn530 and the crystal structure of the N530D variant zHDAC6 revealed binding of a BAS-2-derived mercaptoacetamide that engages the catalytic zinc via strong thiolate-zinc coordination. Leveraging the orientation of BAS-2 binding, we designed a BAS-2-based proteolysis targeting chimera that induced proteasome-dependent HDAC6 degradation in cells, verified by global proteomics. Collectively, these insights clarify species selectivity and demonstrate that BAS-2 acts as a selective, mechanism-based inhibitor of human HDAC6. These discoveries will aid the development of the next generation of selective HDAC6 inhibitors and degraders.