6yb4
From Proteopedia
Crystal structure of human ATAD2 bromodomain in complex with N-(4-bromo-3-(3-methylpyrrolidin-1-yl)sulfonyl)phenyl)-2-(-4-cyclopropyl-4-methyl-2,5-dioxoimidazolidin-1-yl)acetamide
Structural highlights
Function[ATAD2_HUMAN] May be a transcriptional coactivator of the nuclear receptor ESR1 required to induce the expression of a subset of estradiol target genes, such as CCND1, MYC and E2F1. May play a role in the recruitment or occupancy of CREBBP at some ESR1 target gene promoters. May be required for histone hyperacetylation. Involved in the estrogen-induced cell proliferation and cell cycle progression of breast cancer cells.[1] Publication Abstract from PubMedMost bromodomain inhibitors mimic the interactions of the natural acetylated lysine (KAc) histone substrate through key interactions with conserved asparagine and tyrosine residues within the binding pocket. Herein we report the optimisation of a series of phenyl sulfonamides which exhibit a novel mode of binding to non-Bromodomain and Extra Terminal Domain (non-BET) bromodomains through displacement of a normally conserved network of four water molecules. Starting from an initial hit molecule we report its divergent optimisation towards the ATPase family AAA domain containing 2 (ATAD2) and Cats Eye Syndrome Chromosome Region, Candidate 2 (CECR2) domains. This work concludes with the identification of (R)-55 (GSK232), a highly selective, cellularly penetrant CECR2 inhibitor with excellent physicochemical properties. The Optimisation of Potent ATAD2 and CECR2 Bromodomain Inhibitors with an Atypical Binding Mode.,Lucas S, Atkinson SJ, Bamborough P, Barnett HA, Chung CW, Gordon LJ, Mitchell DJ, Phillipou A, Prinjha RK, Sheppard RJ, Tomkinson NCO, Watson RJ, Demont EH J Med Chem. 2020 Apr 22. doi: 10.1021/acs.jmedchem.0c00021. PMID:32321240[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. Loading citation details.. Citations No citations found References
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