5N49

BRPF2 in complex with Compound 7

Summary for 5N49

• Entry DOI: 10.2210/pdb5n49/pdb
• Descriptor: Bromodomain-containing protein 1, 2-(1,3,6-trimethyl-2-oxidanylidene-benzimidazol-5-yl)benzo[de]isoquinoline-1,3-dione (3 entities in total)
• Functional Keywords: bromodomain, chemical probe, transcription
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : O95696
• Total number of polymer chains: 2
• Total formula weight: 31877.40

Authors

Bouche, L.,Christ, C.D.,Siegel, S.,Fernandez-Montalvan, A.E.,Holton, S.J.,Fedorov, O.,ter Laak, A.,Sugawara, T.,Stoeckigt, D.,Tallant, C.,Bennett, J.,Monteiro, O.,Saez, L.D.,Siejka, P.,Meier, J.,Puetter, V.,Weiske, J.,Mueller, S.,Huber, K.V.M.,Hartung, I.V.,Haendler, B. (deposition date: 2017-02-10, release date: 2017-05-03, Last modification date: 2024-05-08)

Primary citation

Bouche, L.,Christ, C.D.,Siegel, S.,Fernandez-Montalvan, A.E.,Holton, S.J.,Fedorov, O.,Ter Laak, A.,Sugawara, T.,Stockigt, D.,Tallant, C.,Bennett, J.,Monteiro, O.,Diaz-Saez, L.,Siejka, P.,Meier, J.,Putter, V.,Weiske, J.,Muller, S.,Huber, K.V.M.,Hartung, I.V.,Haendler, B.
Benzoisoquinolinediones as Potent and Selective Inhibitors of BRPF2 and TAF1/TAF1L Bromodomains.
J. Med. Chem., 60:4002-4022, 2017

PubMed Abstract: Bromodomains (BD) are readers of lysine acetylation marks present in numerous proteins associated with chromatin. Here we describe a dual inhibitor of the bromodomain and PHD finger (BRPF) family member BRPF2 and the TATA box binding protein-associated factors TAF1 and TAF1L. These proteins are found in large chromatin complexes and play important roles in transcription regulation. The substituted benzoisoquinolinedione series was identified by high-throughput screening, and subsequent structure-activity relationship optimization allowed generation of low nanomolar BRPF2 BD inhibitors with strong selectivity against BRPF1 and BRPF3 BDs. In addition, a strong inhibition of TAF1/TAF1L BD2 was measured for most derivatives. The best compound of the series was BAY-299, which is a very potent, dual inhibitor with an IC of 67 nM for BRPF2 BD, 8 nM for TAF1 BD2, and 106 nM for TAF1L BD2. Importantly, no activity was measured for BRD4 BDs. Furthermore, cellular activity was evidenced using a BRPF2- or TAF1-histone H3.3 or H4 interaction assay.

PubMed: 28402630
DOI: 10.1021/acs.jmedchem.7b00306

Experimental method

X-RAY DIFFRACTION (1.94 Å)