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Discovery of New Bromodomain Scaffolds by Biosensor Fragment Screening

DOI: 10.1021/acsmedchemlett.6b00154 DOI Help

Authors: Iva Navratilova (University of Dundee) , Tonia Aristotelous (University of Dundee) , Sarah Picaud (Structural Genomics Consortium, University of Oxford) , Apirat Chaikuad (Structural Genomics Consortium, University of Oxford) , Stefan Knapp (Structural Genomics Consortium, University of Oxford) , Panagis Filappakopoulos (Structural Genomics Consortium, University of Oxford; Ludwig Institute for Cancer Research) , Andrew L. Hopkins (University of Dundee)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Medicinal Chemistry Letters , VOL 7 , PAGES 1213 - 1218

State: Published (Approved)
Published: December 2016

Abstract: The discovery of novel bromodomain inhibitors by fragment screening is complicated by the presence of dimethyl sulfoxide (DMSO), an acetyl-lysine mimetic, that can compromise the detection of low affinity fragments. We demonstrate surface plasmon resonance as a primary fragment screening approach for the discovery of novel bromodomain scaffolds, by describing a protocol to overcome the DMSO interference issue. We describe the discovery of several novel small molecules scaffolds that inhibit the bromodomains PCAF, BRD4, and CREBBP, representing canonical members of three out of the seven subfamilies of bromodomains. High-resolution crystal structures of the complexes of key fragments binding to BRD4(1), CREBBP, and PCAF were determined to provide binding mode data to aid the development of potent and selective inhibitors of PCAF, CREBBP, and BRD4.

Journal Keywords: BRD4; Bromodomains; CREBBP; fragment screening; PCAF; surface plasmon resonance

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I03-Macromolecular Crystallography