4UIZ

N-TERMINAL BROMODOMAIN OF HUMAN BRD4 WITH 7-(3,4-dimethoxyphenyl)-2-(4-methanesulfonylpiperazine-1-carbonyl)-5-methyl-4H,5H-thieno-3,2-c- pyridin-4-one

Summary for 4UIZ

• Entry DOI: 10.2210/pdb4uiz/pdb
• Related: 4UIT 4UIU 4UIV 4UIW 4UIX 4UIY
• Descriptor: BROMODOMAIN-CONTAINING PROTEIN 4, 1,2-ETHANEDIOL, 7-(3,4-dimethoxyphenyl)-5-methyl-2-(4-methylsulfonylpiperazin-1-yl)carbonyl-thieno[3,2-c]pyridin-4-one, ... (4 entities in total)
• Functional Keywords: transcription, inhibitor, histone, epigenetic reader, bromodomain, brd4, bromodomain containing protein 4, antagonist
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Nucleus: O60885
• Total number of polymer chains: 1
• Total formula weight: 15715.10

Authors

Chung, C.,Theodoulou, N.T.,Bamborough, P.,Humphreys, P.G. (deposition date: 2015-04-03, release date: 2015-04-22, Last modification date: 2024-05-08)

Primary citation

Theodoulou, N.H.,Bamborough, P.,Bannister, A.J.,Becher, I.,Bit, R.A.,Che, K.H.,Chung, C.,Dittmann, A.,Drewes, G.,Drewry, D.H.,Gordon, L.,Grandi, P.,Leveridge, M.,Lindon, M.,Michon, A.,Molnar, J.,Robson, S.C.,Tomkinson, N.C.O.,Kouzarides, T.,Prinjha, R.K.,Humphreys, P.G.
The Discovery of I-Brd9, a Selective Cell Active Chemical Probe for Bromodomain Containing Protein 9 Inhibition.
J.Med.Chem., 59:1425-, 2016

PubMed Abstract: Acetylation of histone lysine residues is one of the most well-studied post-translational modifications of chromatin, selectively recognized by bromodomain "reader" modules. Inhibitors of the bromodomain and extra terminal domain (BET) family of bromodomains have shown profound anticancer and anti-inflammatory properties, generating much interest in targeting other bromodomain-containing proteins for disease treatment. Herein, we report the discovery of I-BRD9, the first selective cellular chemical probe for bromodomain-containing protein 9 (BRD9). I-BRD9 was identified through structure-based design, leading to greater than 700-fold selectivity over the BET family and 200-fold over the highly homologous bromodomain-containing protein 7 (BRD7). I-BRD9 was used to identify genes regulated by BRD9 in Kasumi-1 cells involved in oncology and immune response pathways and to the best of our knowledge, represents the first selective tool compound available to elucidate the cellular phenotype of BRD9 bromodomain inhibition.

PubMed: 25856009
DOI: 10.1021/ACS.JMEDCHEM.5B00256

Experimental method

X-RAY DIFFRACTION (1.19 Å)