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J Med Chem. 2017 Nov 9;60(21):9090-9096. doi: 10.1021/acs.jmedchem.7b00933. Epub 2017 Oct 27.

Small Molecule Antagonists of the Interaction between the Histone Deacetylase 6 Zinc-Finger Domain and Ubiquitin.

Author information

1
Structural Genomics Consortium, University of Toronto , MaRS South Tower, Suite 700, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
2
Diamond Light Source Ltd. , Harwell Science and Innovation Campus, Didcot OX11 0QX, U.K.
3
Department of Chemistry, Davenport Chemical Laboratories, University of Toronto , 80 St. George Street, Toronto, Ontario M5S 3H6, Canada.
4
GrandPharma , Wuhan City Plaza, 23rd Floor, 160 Qiaokou Road, Wuhan, Hubei 430032, China.
5
Department of Pharmacology and Toxicology, University of Toronto , Toronto, Ontario M5S 1A8, Canada.
6
Structural Genomics Consortium, University of Oxford , Roosevelt Drive, Oxford OX11 9HP, U.K.

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.

PMID:
29019676
DOI:
10.1021/acs.jmedchem.7b00933
[Indexed for MEDLINE]

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