Discovery of New Bromodomain Scaffolds by Biosensor Fragment Screening

ACS Med Chem Lett. 2016 Sep 20;7(12):1213-1218. doi: 10.1021/acsmedchemlett.6b00154. eCollection 2016 Dec 8.


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.

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