4Z6H

Crystal structure of BRD9 bromodomain in complex with a valerolactam quinolone ligand

Summary for 4Z6H

• Entry DOI: 10.2210/pdb4z6h/pdb
• Descriptor: Bromodomain-containing protein 9, 1,4-dimethyl-7-(2-oxopiperidin-1-yl)quinolin-2(1H)-one (3 entities in total)
• Functional Keywords: lysine-acetylated histone binding, chromatin regulator, transcription, bromodomain, structural genomics, structural genomics consortium, sgc
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 29040.18

Authors

Tallant, C.,Structural Genomics Consortium (SGC),Clark, P.G.K.,Vieira, L.C.C.,Krojer, T.,Nunez-Alonso, G.,Picaud, S.,Fedorov, O.,Dixon, D.J.,von Delft, F.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Brennan, P.E.,Knapp, S. (deposition date: 2015-04-05, release date: 2015-05-20, Last modification date: 2024-01-10)

Primary citation

Clark, P.G.,Vieira, L.C.,Tallant, C.,Fedorov, O.,Singleton, D.C.,Rogers, C.M.,Monteiro, O.P.,Bennett, J.M.,Baronio, R.,Muller, S.,Daniels, D.L.,Mendez, J.,Knapp, S.,Brennan, P.E.,Dixon, D.J.
LP99: Discovery and Synthesis of the First Selective BRD7/9 Bromodomain Inhibitor.
Angew.Chem.Int.Ed.Engl., 54:6217-6221, 2015

PubMed Abstract: The bromodomain-containing proteins BRD9 and BRD7 are part of the human SWI/SNF chromatin-remodeling complexes BAF and PBAF. To date, no selective inhibitor for BRD7/9 has been reported despite its potential value as a biological tool or as a lead for future therapeutics. The quinolone-fused lactam LP99 is now reported as the first potent and selective inhibitor of the BRD7 and BRD9 bromodomains. Development of LP99 from a fragment hit was expedited through balancing structure-based inhibitor design and biophysical characterization against tractable chemical synthesis: Complexity-building nitro-Mannich/lactamization cascade processes allowed for early structure-activity relationship studies whereas an enantioselective organocatalytic nitro-Mannich reaction enabled the synthesis of the lead scaffold in enantioenriched form and on scale. This epigenetic probe was shown to inhibit the association of BRD7 and BRD9 to acetylated histones in vitro and in cells. Moreover, LP99 was used to demonstrate that BRD7/9 plays a role in regulating pro-inflammatory cytokine secretion.

PubMed: 25864491
DOI: 10.1002/anie.201501394

Experimental method

X-RAY DIFFRACTION (1.8 Å)