Format

Send to

Choose Destination
J Med Chem. 2017 Jul 13;60(13):5349-5363. doi: 10.1021/acs.jmedchem.6b01839. Epub 2017 May 12.

Structure-Based Design of Highly Selective Inhibitors of the CREB Binding Protein Bromodomain.

Author information

1
Medicine Design, Pfizer , 610 Main Street, Cambridge Massachusetts 02139, United States.
2
Medicine Design, Pfizer , Eastern Point Road, Groton Connecticut 06340, United States.
3
Structural Biology and Biophysics, Medicine Design, Pfizer , Eastern Point Road, Groton Connecticut 06340, United States.
4
Primary Pharmacology Group, Pfizer , Eastern Point Road, Groton Connecticut 06340, United States.
5
Evotec (UK) Ltd. , 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, UK.
6
Structural Genomics Consortium, Target Discovery Institute, ARUK Oxford Drug Discovery Institute, University of Oxford , NDM Research Building, Roosevelt Drive, Oxford OX3 7FZ, U.K.
7
Rare Disease Research Unit, Pfizer , 610 Main Street, Cambridge Massachusetts 02139, United States.

Abstract

Chemical probes are required for preclinical target validation to interrogate novel biological targets and pathways. Selective inhibitors of the CREB binding protein (CREBBP)/EP300 bromodomains are required to facilitate the elucidation of biology associated with these important epigenetic targets. Medicinal chemistry optimization that paid particular attention to physiochemical properties delivered chemical probes with desirable potency, selectivity, and permeability attributes. An important feature of the optimization process was the successful application of rational structure-based drug design to address bromodomain selectivity issues (particularly against the structurally related BRD4 protein).

PMID:
28375629
DOI:
10.1021/acs.jmedchem.6b01839
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for American Chemical Society
Loading ...
Support Center