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J Med Chem. 2016 Feb 25;59(4):1648-53. doi: 10.1021/acs.jmedchem.5b01719. Epub 2016 Jan 13.

Structure-Based Identification of Inhibitory Fragments Targeting the p300/CBP-Associated Factor Bromodomain.

Author information

1
Nuffield Department of Clinical Medicine, Structural Genomics Consortium and Target Discovery Institute, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, U.K.
2
Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge CB2 1EW, U.K.
3
Leiden Institute of Chemistry, Leiden University , Einsteinweg 55, 2333 CC Leiden, Netherlands.
4
ZoBio , Einsteinweg 55, 2333 CC Leiden, Netherlands.
5
Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University and Buchmann Institute for Molecular Life Sciences , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.

Abstract

The P300/CBP-associated factor plays a central role in retroviral infection and cancer development, and the C-terminal bromodomain provides an opportunity for selective targeting. Here, we report several new classes of acetyl-lysine mimetic ligands ranging from mM to low micromolar affinity that were identified using fragment screening approaches. The binding modes of the most attractive fragments were determined using high resolution crystal structures providing chemical starting points and structural models for the development of potent and selective PCAF inhibitors.

PMID:
26731131
PMCID:
PMC4770306
DOI:
10.1021/acs.jmedchem.5b01719
[Indexed for MEDLINE]
Free PMC Article

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