| Literature DB >> 34236185 |
Huarui Cui1, Angela S Carlson1, Mary A Schleiff2, Anand Divakaran3, Jorden A Johnson1, Caroline R Buchholz3, Huda Zahid1, Nora R Vail1, Ke Shi4, Hideki Aihara4, Daniel A Harki1,3, Grover P Miller2, Joseph J Topczewski1, William C K Pomerantz1,3.
Abstract
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-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.Entities:
Mesh：
Substances：
Year: 2021 PMID： 34236185 PMCID： PMC8491147 DOI： 10.1021/acs.jmedchem.1c00933
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 8.039