4J0R

Crystal Structure of the first bromodomain of human BRD4 in complex with a 3,5-dimethylisoxazol ligand

Summary for 4J0R

• Entry DOI: 10.2210/pdb4j0r/pdb
• Related: 4J0S
• Descriptor: Bromodomain-containing protein 4, 1,2-ETHANEDIOL, 3-(3,5-dimethyl-1,2-oxazol-4-yl)-5-[(R)-hydroxy(phenyl)methyl]phenol, ... (5 entities in total)
• Functional Keywords: brd4, bromodomain containing protein 4, cap, hunk1, mcap, mitotic chromosome associated protein, isoxazole, structural genomics consortium, sgc, signaling protein
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus (By similarity): O60885
• Total number of polymer chains: 1
• Total formula weight: 15769.89

Authors

Filippakopoulos, P.,Picaud, S.,Qi, J.,Felletar, I.,Hewings, D.S.,von Delft, F.,Conway, S.J.,Bountra, C.,Arrowsmith, C.H.,Edwards, A.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2013-01-31, release date: 2013-02-13, Last modification date: 2023-09-20)

Primary citation

Hewings, D.S.,Fedorov, O.,Filippakopoulos, P.,Martin, S.,Picaud, S.,Tumber, A.,Wells, C.,Olcina, M.M.,Freeman, K.,Gill, A.,Ritchie, A.J.,Sheppard, D.W.,Russell, A.J.,Hammond, E.M.,Knapp, S.,Brennan, P.E.,Conway, S.J.
Optimization of 3,5-dimethylisoxazole derivatives as potent bromodomain ligands.
J.Med.Chem., 56:3217-3227, 2013

PubMed Abstract: The bromodomain protein module, which binds to acetylated lysine, is emerging as an important epigenetic therapeutic target. We report the structure-guided optimization of 3,5-dimethylisoxazole derivatives to develop potent inhibitors of the BET (bromodomain and extra terminal domain) bromodomain family with good ligand efficiency. X-ray crystal structures of the most potent compounds reveal key interactions required for high affinity at BRD4(1). Cellular studies demonstrate that the phenol and acetate derivatives of the lead compounds showed strong antiproliferative effects on MV4;11 acute myeloid leukemia cells, as shown for other BET bromodomain inhibitors and genetic BRD4 knockdown, whereas the reported compounds showed no general cytotoxicity in other cancer cell lines tested.

PubMed: 23517011
DOI: 10.1021/jm301588r

Experimental method

X-RAY DIFFRACTION (1.72 Å)