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Small molecule antagonists of the interaction between the histone deacetylase 6 zinc-finger domain and ubiquitin

DOI: 10.1021/acs.jmedchem.7b00933 DOI Help

Authors: Rachel J. Harding (Structural Genomics Consortium, University of Toronto) , Renato Ferreira De Freitas (Structural Genomics Consortium, University of Toronto) , Patrick Collins (Diamond Light Source) , Ivan Franzoni (University of Toronto) , Mani Ravichandran (Structural Genomics Consortium, University of Toronto) , Hui Ouyang (GrandPharma) , Kevin A. Juarez-Ornelas (University of Toronto) , Mark Lautens (University of Toronto) , Matthieu Schapira (Structural Genomics Consortium, University of Toronto) , Frank Von Delft (Diamond Light Source; Structural Genomics Consortium, University of Oxford) , Vijayaratnam Santhakumar (Structural Genomics Consortium, University of Toronto) , Cheryl H. Arrowsmith (Structural Genomics Consortium, University of Toronto;)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: October 2017

Abstract: Inhibitors of HDAC6 have attractive potential in numerous cancers. HDAC6 inhibitors to date target the catalytic domains, but targeting the unique zinc-finger ubiquitin-binding domain (Zf-UBD) of HDAC6 may be an attractive alternative strategy. We developed X-ray crystallography and biophysical assays to identify and characterize small molecules capable of binding to the Zf-UBD and competing with ubiquitin binding. Our results revealed two adjacent ligand-able pockets of HDAC6 Zf-UBD and the first functional ligands for this domain.

Subject Areas: Chemistry, Biology and Bio-materials, Medicine

Instruments: I04-Macromolecular Crystallography

Added On: 16/10/2017 10:06

Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)