4-Methyl-1,2,3-Triazoles as N -Acetyl-Lysine Mimics Afford Potent BET Bromodomain Inhibitors with Improved Selectivity.

Autor: Cui H; Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States., Carlson AS; Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States., Schleiff MA; Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, Arkansas 72205, United States., Divakaran A; Department of Medicinal Chemistry, University of Minnesota, 2231 Sixth Street SE, Minneapolis, Minnesota 55455, United States., Johnson JA; Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States., Buchholz CR; Department of Medicinal Chemistry, University of Minnesota, 2231 Sixth Street SE, Minneapolis, Minnesota 55455, United States., Zahid H; Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States., Vail NR; Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States., Shi K; Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, 321 Church Street SE, Minneapolis, Minnesota 55455, United States., Aihara H; Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, 321 Church Street SE, Minneapolis, Minnesota 55455, United States., Harki DA; Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States.; Department of Medicinal Chemistry, University of Minnesota, 2231 Sixth Street SE, Minneapolis, Minnesota 55455, United States., Miller GP; Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, Arkansas 72205, United States., Topczewski JJ; Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States., Pomerantz WCK; Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States.; Department of Medicinal Chemistry, University of Minnesota, 2231 Sixth Street SE, Minneapolis, Minnesota 55455, United States.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2021 Jul 22; Vol. 64 (14), pp. 10497-10511. Date of Electronic Publication: 2021 Jul 08.
DOI: 10.1021/acs.jmedchem.1c00933
Abstrakt: 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 K d 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-α-stimulated A549 cells. These data indicate that DW34 and 26 are new leads to investigate the anticancer and anti-inflammatory activity of BET proteins.
Databáze: MEDLINE
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