4z1s
Crystal structure of the first bromodomain of human BRD4 with benzotriazolo-diazepine scaffold
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 PubMedInhibition of the bromodomains of the BET family, of which BRD4 is a member, has been shown to decrease myc and interleukin (IL) 6 in vivo, markers that are of therapeutic relevance to cancer and inflammatory disease, respectively. Herein we report substituted benzo[b]isoxazolo[4,5-d]azepines and benzotriazolo[4,3-d][1,4]diazepines as fragment-derived novel inhibitors of the bromodomain of BRD4. Compounds from these series were potent and selective in cells, and subsequent optimization of microsomal stability yielded representatives that demonstrated dose- and time-dependent reduction of plasma IL-6 in mice. Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains.,Taylor AM, Vaswani RG, Gehling VS, Hewitt MC, Leblanc Y, Audia JE, Bellon S, Cummings RT, Cote A, Harmange JC, Jayaram H, Joshi S, Lora JM, Mertz JA, Neiss A, Pardo E, Nasveschuk CG, Poy F, Sandy P, Setser JW, Sims RJ 3rd, Tang Y, Albrecht BK ACS Med Chem Lett. 2015 Mar 25;7(2):145-50. doi: 10.1021/ml500411h. eCollection, 2016 Feb 11. PMID:26985289[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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