2. Academic Validation
  3. Discovery and Characterization of a Chemical Probe Targeting the Zinc-Finger Ubiquitin-Binding Domain of HDAC6

Discovery and Characterization of a Chemical Probe Targeting the Zinc-Finger Ubiquitin-Binding Domain of HDAC6

  • J Med Chem. 2023 Aug 10;66(15):10273-10288. doi: 10.1021/acs.jmedchem.3c00314.
Rachel J Harding 1 2,  Ivan Franzoni 3 4,  Mandeep K Mann 1,  Magdalena M Szewczyk 1,  Bijan Mirabi 3,  Renato Ferreira de Freitas 1,  Dominic D G Owens 1,  Suzanne Ackloo 1,  Alexej Scheremetjew 3,  Kevin A Juarez-Ornelas 3,  Randy Sanichar 3,  Rachel J Baker 3,  Christian Dank 3,  Peter J Brown 1,  Dalia Barsyte-Lovejoy 1 2,  Vijayaratnam Santhakumar 1,  Matthieu Schapira 1 2,  Mark Lautens 3,  Cheryl H Arrowsmith 1 5
Affiliations

Affiliations

  • 1 Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
  • 2 Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
  • 3 Davenport Research Laboratories, Department of Chemistry, University of Toronto, Toronto, Ontario M5S 3H6, Canada.
  • 4 Valence Discovery Inc., 6666 Rue St-Urbain, Suite 200, Montreal, Quebec H2S 3H1, Canada.
  • 5 Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
PMID: 37499118 DOI: 10.1021/acs.jmedchem.3c00314
Abstract

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

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-155697
    99.3%, HDAC6-UBD Antagonist