TY - JOUR
T1 - Discovery of New Bromodomain Scaffolds by Biosensor Fragment Screening
AU - Navratilova, Iva
AU - Aristotelous, Tonia
AU - Picaud, Sarah
AU - Chaikuad, Apirat
AU - Knapp, Stefan
AU - Filappakopoulos, Panagis
AU - Hopkins, Andrew L.
N1 - This work is funded by the MSD Scottish Life Sciences Fund (to I.N.), in part by grants HL16037. P.F, S.P., A.C., and S.K. are supported by the SGC. The SGC is a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, GenomeCanada, Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD grant no. 115766], Janssen, Merck & Co., Novartis Pharma AG, Ontario Ministry of Economic Development and Innovation, Pfizer, Sao Paulo Research Foundation-
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FAPESP, Takeda, and Wellcome Trust (092809/Z/10/Z). P.F. and S.P. are supported by a Wellcome Career Development Fellowship (095751/Z/11/Z). A.H. was support in part by SULSA (HR07019).
PY - 2016/12/8
Y1 - 2016/12/8
N2 - 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.
AB - 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.
KW - BRD4
KW - Bromodomains
KW - CREBBP
KW - fragment screening
KW - PCAF
KW - surface plasmon resonance
UR - http://www.scopus.com/inward/record.url?scp=85003906189&partnerID=8YFLogxK
U2 - 10.1021/acsmedchemlett.6b00154
DO - 10.1021/acsmedchemlett.6b00154
M3 - Article
C2 - 27994766
AN - SCOPUS:85003906189
SN - 1948-5875
VL - 7
SP - 1213
EP - 1218
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
IS - 12
ER -
