5khm | pdb_00005khm
The first BET bromodomain of BRD4 bound to compound 13 in a bivalent manner
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 PubMedHere we report the discovery and optimization of a series of bivalent bromodomain and extraterminal inhibitors. Starting with the observation of BRD4 activity of compounds from a previous program, the compounds were optimized for BRD4 potency and physical properties. The optimized compound from this campaign exhibited excellent pharmacokinetic profile and exhibited high potency in vitro and in vivo effecting c-Myc downregulation and tumor growth inhibition in xenograft studies. This compound was selected as the development candidate, AZD5153. The series showed enhanced potency as a result of bivalent binding and a clear correlation between BRD4 activity and cellular potency. Optimization of a Series of Bivalent Triazolopyridazine Based Bromodomain and Extraterminal Inhibitors: The Discovery of (3R)-4-[2-[4-[1-(3-Methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-4-piperidyl]phen oxy]ethyl]-1,3-dimethyl-piperazin-2-one (AZD5153).,Bradbury RH, Callis R, Carr GR, Chen H, Clark E, Feron L, Glossop S, Graham MA, Hattersley M, Jones C, Lamont SG, Ouvry G, Patel A, Patel J, Rabow AA, Roberts CA, Stokes S, Stratton N, Walker GE, Ward L, Whalley D, Whittaker D, Wrigley G, Waring MJ J Med Chem. 2016 Sep 8;59(17):7801-17. doi: 10.1021/acs.jmedchem.6b00070. Epub, 2016 Aug 24. PMID:27528113[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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