4Z1Q

Crystal structure of the first bromodomain of human BRD4 bound to benzotriazolo-diazepine scaffold

Summary for 4Z1Q

• Entry DOI: 10.2210/pdb4z1q/pdb
• Descriptor: Bromodomain-containing protein 4, 5-[(4R)-6-(4-chlorophenyl)-1,4-dimethyl-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-8-yl]pyridin-2-amine (3 entities in total)
• Functional Keywords: bromodomain, transcription
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus: O60885
• Total number of polymer chains: 2
• Total formula weight: 30828.26

Authors

Setser, J.W.,Poy, F.,Tang, Y.,Bellon, S.F. (deposition date: 2015-03-27, release date: 2015-04-08, Last modification date: 2024-03-06)

Primary citation

Taylor, A.M.,Vaswani, R.G.,Gehling, V.S.,Hewitt, M.C.,Leblanc, Y.,Audia, J.E.,Bellon, S.,Cummings, R.T.,Cote, A.,Harmange, J.C.,Jayaram, H.,Joshi, S.,Lora, J.M.,Mertz, J.A.,Neiss, A.,Pardo, E.,Nasveschuk, C.G.,Poy, F.,Sandy, P.,Setser, J.W.,Sims, R.J.,Tang, Y.,Albrecht, B.K.
Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains.
Acs Med.Chem.Lett., 7:145-150, 2016

PubMed Abstract: Inhibition of the bromodomains of the BET family, of which BRD4 is a member, has been shown to decrease myc and interleukin (IL) 6 in vivo, markers that are of therapeutic relevance to cancer and inflammatory disease, respectively. Herein we report substituted benzo[b]isoxazolo[4,5-d]azepines and benzotriazolo[4,3-d][1,4]diazepines as fragment-derived novel inhibitors of the bromodomain of BRD4. Compounds from these series were potent and selective in cells, and subsequent optimization of microsomal stability yielded representatives that demonstrated dose- and time-dependent reduction of plasma IL-6 in mice.

PubMed: 26985289
DOI: 10.1021/ml500411h

Experimental method

X-RAY DIFFRACTION (1.399 Å)