4IR4

Crystal Structure of the bromodomain of human BAZ2B in complex with 1-[7-(morpholin-4-yl)-1-(pyridin-2-yl)indolizin-3-yl]ethanone (GSK2834113A)

Summary for 4IR4

• Entry DOI: 10.2210/pdb4ir4/pdb
• Related: 4IR3 4IR5 4IR6 4RVR
• Descriptor: Bromodomain adjacent to zinc finger domain protein 2B, 1-[7-(morpholin-4-yl)-1-(pyridin-2-yl)indolizin-3-yl]ethanone, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: sgc, structural genomics consortium, transcription, bromodomain, acetylated lysine binding protein, kiaa1476, walp4
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus : Q9UIF8
• Total number of polymer chains: 1
• Total formula weight: 14436.57

Authors

Chaikuad, A.,Felletar, I.,Chung, C.W.,Drewry, D.,Chen, P.,Filippakopoulos, P.,Fedorov, O.,Krojer, T.,von Delft, F.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2013-01-14, release date: 2013-01-23, Last modification date: 2023-09-20)

Primary citation

Chen, P.,Chaikuad, A.,Bamborough, P.,Bantscheff, M.,Bountra, C.,Chung, C.W.,Fedorov, O.,Grandi, P.,Jung, D.,Lesniak, R.,Lindon, M.,Muller, S.,Philpott, M.,Prinjha, R.,Rogers, C.,Selenski, C.,Tallant, C.,Werner, T.,Willson, T.M.,Knapp, S.,Drewry, D.H.
Discovery and Characterization of GSK2801, a Selective Chemical Probe for the Bromodomains BAZ2A and BAZ2B.
J.Med.Chem., 59:1410-1424, 2016

PubMed Abstract: Bromodomains are acetyl-lysine specific protein interaction domains that have recently emerged as a new target class for the development of inhibitors that modulate gene transcription. The two closely related bromodomain containing proteins BAZ2A and BAZ2B constitute the central scaffolding protein of the nucleolar remodeling complex (NoRC) that regulates the expression of noncoding RNAs. However, BAZ2 bromodomains have low predicted druggability and so far no selective inhibitors have been published. Here we report the development of GSK2801, a potent, selective and cell active acetyl-lysine competitive inhibitor of BAZ2A and BAZ2B bromodomains as well as the inactive control compound GSK8573. GSK2801 binds to BAZ2 bromodomains with dissociation constants (KD) of 136 and 257 nM for BAZ2B and BAZ2A, respectively. Crystal structures demonstrated a canonical acetyl-lysine competitive binding mode. Cellular activity was demonstrated using fluorescent recovery after photobleaching (FRAP) monitoring displacement of GFP-BAZ2A from acetylated chromatin. A pharmacokinetic study in mice showed that GSK2801 had reasonable in vivo exposure after oral dosing, with modest clearance and reasonable plasma stability. Thus, GSK2801 represents a versatile tool compound for cellular and in vivo studies to understand the role of BAZ2 bromodomains in chromatin biology.

PubMed: 25799074
DOI: 10.1021/acs.jmedchem.5b00209

Experimental method

X-RAY DIFFRACTION (2.05 Å)