6DF7

TAF1-BD2 in complex with Cpd27 (6-(but-3-en-1-yl)-4-(1-methyl-6-(morpholine-4-carbonyl)-1H-benzo[d]imidazol-4-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one)

Summary for 6DF7

• Entry DOI: 10.2210/pdb6df7/pdb
• Related: 6DF4
• Descriptor: Transcription initiation factor TFIID subunit, 6-(but-3-en-1-yl)-4-[1-methyl-6-(morpholine-4-carbonyl)-1H-benzimidazol-4-yl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (3 entities in total)
• Functional Keywords: taf1-bd2, bromodomain, small molecule inhibitor, sbdd, transcription-inhibitor complex, transcription/inhibitor
• Biological source: Oryctolagus cuniculus (Rabbit)
• Total number of polymer chains: 2
• Total formula weight: 39468.06

Authors

Murray, J.M. (deposition date: 2018-05-14, release date: 2018-11-14, Last modification date: 2023-10-11)

Primary citation

Wang, S.,Tsui, V.,Crawford, T.D.,Audia, J.E.,Burdick, D.J.,Beresini, M.H.,Cote, A.,Cummings, R.,Duplessis, M.,Flynn, E.M.,Hewitt, M.C.,Huang, H.R.,Jayaram, H.,Jiang, Y.,Joshi, S.,Murray, J.,Nasveschuk, C.G.,Pardo, E.,Poy, F.,Romero, F.A.,Tang, Y.,Taylor, A.M.,Wang, J.,Xu, Z.,Zawadzke, L.E.,Zhu, X.,Albrecht, B.K.,Magnuson, S.R.,Bellon, S.,Cochran, A.G.
GNE-371, a Potent and Selective Chemical Probe for the Second Bromodomains of Human Transcription-Initiation-Factor TFIID Subunit 1 and Transcription-Initiation-Factor TFIID Subunit 1-like.
J. Med. Chem., 61:9301-9315, 2018

PubMed Abstract: The biological functions of the dual bromodomains of human transcription-initiation-factor TFIID subunit 1 (TAF1(1,2)) remain unknown, although TAF1 has been identified as a potential target for oncology research. Here, we describe the discovery of a potent and selective in vitro tool compound for TAF1(2), starting from a previously reported lead. A cocrystal structure of lead compound 2 bound to TAF1(2) enabled structure-based design and structure-activity-relationship studies that ultimately led to our in vitro tool compound, 27 (GNE-371). Compound 27 binds TAF1(2) with an IC of 10 nM while maintaining excellent selectivity over other bromodomain-family members. Compound 27 is also active in a cellular-TAF1(2) target-engagement assay (IC = 38 nM) and exhibits antiproliferative synergy with the BET inhibitor JQ1, suggesting engagement of endogenous TAF1 by 27 and further supporting the use of 27 in mechanistic and target-validation studies.

PubMed: 30289257
DOI: 10.1021/acs.jmedchem.8b01225

Experimental method

X-RAY DIFFRACTION (2 Å)