PDB 4J0S deposited: 2013-01-31 modified: 2013-05-29
Title Crystal Structure of the first bromodomain of human BRD4 in complex with a 3,5-dimethylisoxazol ligand
Authors Brennan, P.E., Conway, S.J., Fedorov, O., Filippakopoulos, P., Freeman, K., Gill, A., Hammond, E.M., Hewings, D.S., Knapp, S., Martin, S., Olcina, M.M., Picaud, S., Ritchie, A.J., Russell, A.J., Sheppard, D.W., Tumber, A., Wells, C.
Structure factors resolution None rfactor None rfree None
Related PDB Entries 4J0R

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.

J.Med.Chem. 2013 Apr; 56(8):3217-3227 doi:10.1021/jm301588r

Cross References
Database source Identifier Description
ChEMBL Document CHEMBL2331285
PubMed 23517011 JMCMAR
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
4J0S/0 4J0S 0 monomer 0 1 5 1178