4j0s
From Proteopedia
Crystal Structure of the first bromodomain of human BRD4 in complex with a 3,5-dimethylisoxazol ligand
Structural highlights
DiseaseBRD4_HUMAN Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein.[1] [2] FunctionBRD4_HUMAN Plays a role in a process governing chromosomal dynamics during mitosis (By similarity). Publication Abstract from PubMedThe 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. Optimization of 3,5-dimethylisoxazole derivatives as potent bromodomain ligands.,Hewings DS, Fedorov O, Filippakopoulos P, Martin S, Picaud S, Tumber A, Wells C, Olcina MM, Freeman K, Gill A, Ritchie AJ, Sheppard DW, Russell AJ, Hammond EM, Knapp S, Brennan PE, Conway SJ J Med Chem. 2013 Apr 25;56(8):3217-27. doi: 10.1021/jm301588r. Epub 2013 Apr 5. PMID:23517011[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Homo sapiens | Large Structures | Arrowsmith CH | Bountra C | Conway SJ | Edwards A | Felletar I | Filippakopoulos P | Hewings DS | Knapp S | Picaud S | Qi J | Von Delft F
