Discovery and characterization of a chemical probe targeting the zinc-finger ubiquitin-binding domain of HDAC6

• DOI: 10.1101/2023.02.21.525740
• Publication Date: 2023-02-22T19:40:15Z
• Authors: Rachel J. Harding; Ivan Franzoni; Mandeep K. Mann; Magdalena M. Szew...; Bijan Mirabi; Dominic D.G Owens; Suzanne Ackloo; Alexej Scheremetjew; Kevin A. Juarez-O...; Randy Sanichar; Rachel J. Baker; Christian Dank; Peter J. Brown; Dalia Barsyte-Lov...; Vijayaratnam Sant...; Matthieu Schapira; Mark Lautens; Cheryl H. Arrowsmith
• Keywords: HDAC6

ABSTRACT Histone deacetylase 6 (HDAC6) inhibition is an attractive strategy for treating numerous cancers, and HDAC6 catalytic inhibitors are currently in clinical trials. The zinc-finger ubiquitin-binding domain (UBD) binds free C-terminal diglycine motifs of unanchored ubiquitin polymer chains protein aggregates, playing important role autophagy aggresome assembly. However, targeting this with small molecule antagonists remains underdeveloped avenue HDAC6-focused drug discovery. We report SGC-UBD253 (25), a chemical probe potently HDAC6-UBD vitro selectivity over nine other UBDs, except weak USP16 binding. In cells, 25 effective antagonist at 1 µM, marked proteome-wide selectivity. identified SGC-UBD253N ( 32 ), methylated derivative which 300-fold less active, serving as negative control. Together, could enable further exploration the biological function UBD investigation therapeutic potential domain.