7mls | pdb_00007mls

X-ray crystal structure of human BRD4(D1) in complex with 2-(2,5-dibromophenoxy)-6-[4-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-5-yl]pyridine (compound 23)

spinqualitylabelsall models 7mls, resolution 1.26Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7mls is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CL, EDO, ZHM Gene: BRD4, HUNK1 (HUMAN) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [BRD4_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. Function [BRD4_HUMAN] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity). Publication Abstract from PubMed The bromodomain and extra terminal (BET) protein family recognizes acetylated lysines within histones and transcription factors using two N-terminal bromodomains, D1 and D2. The protein-protein interactions between BET bromodomains, acetylated histones, and transcription factors are therapeutic targets for BET-related diseases, including inflammatory disease and cancer. Prior work demonstrated that methylated-1,2,3-triazoles are suitable N-acetyl lysine mimetics for BET inhibition. Here we describe a structure-activity relationship study of triazole-based inhibitors that improve affinity, D1 selectivity, and microsomal stability. These outcomes were accomplished by targeting a nonconserved residue, Asp144 and a conserved residue, Met149, on BRD4 D1. The lead inhibitors DW34 and 26 have a BRD4 D1 Kd of 12 and 6.4 nM, respectively. Cellular activity was demonstrated through suppression of c-Myc expression in MM.1S cells and downregulation of IL-8 in TNF-alpha-stimulated A549 cells. These data indicate that DW34 and 26 are new leads to investigate the anticancer and anti-inflammatory activity of BET proteins. 4-Methyl-1,2,3-Triazoles as N-Acetyl-Lysine Mimics Afford Potent BET Bromodomain Inhibitors with Improved Selectivity.,Cui H, Carlson AS, Schleiff MA, Divakaran A, Johnson JA, Buchholz CR, Zahid H, Vail NR, Shi K, Aihara H, Harki DA, Miller GP, Topczewski JJ, Pomerantz WCK J Med Chem. 2021 Jul 22;64(14):10497-10511. doi: 10.1021/acs.jmedchem.1c00933., Epub 2021 Jul 8. PMID:34236185 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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