Peer-Reviewed Publication
J Med Chem2023;66(15):10273-10288.August 10, 2023Journal Article
Discovery and Characterization of a Chemical Probe Targeting the Zinc-Finger Ubiquitin-Binding Domain of HDAC6.
Rachel J Harding1,2, Ivan Franzoni3,4, Mandeep K Mann1, Magdalena M Szewczyk1, Bijan Mirabi3, Renato Ferreira de Freitas1, Dominic D G Owens1, Suzanne Ackloo1, Alexej Scheremetjew3, Kevin A Juarez-Ornelas3, Randy Sanichar3, Rachel J Baker3, Christian Dank3, Peter J Brown1, Dalia Barsyte-Lovejoy1,2, Vijayaratnam Santhakumar1, Matthieu Schapira1,2, Mark Lautens3, Cheryl H Arrowsmith1,5
1Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
2Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
3Davenport Research Laboratories, Department of Chemistry, University of Toronto, Toronto, Ontario M5S 3H6, Canada.
4Valence Discovery Inc., 6666 Rue St-Urbain, Suite 200, Montreal, Quebec H2S 3H1, Canada.
5Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
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…
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