4-Methyl-1,2,3-Triazoles as N-Acetyl-Lysine Mimics Afford Potent BET Bromodomain Inhibitors with Improved Selectivity.
Huarui CuiAngela S CarlsonMary A SchleiffAnand DivakaranJorden A JohnsonCaroline R BuchholzHuda ZahidNora R VailKe ShiHideki AiharaDaniel A HarkiGrover P MillerJoseph J TopczewskiWilliam C K PomerantzPublished in: Journal of medicinal chemistry (2021)
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.
Keyphrases
- protein protein
- transcription factor
- induced apoptosis
- cell cycle arrest
- amino acid
- oxidative stress
- rheumatoid arthritis
- poor prognosis
- endoplasmic reticulum stress
- signaling pathway
- type diabetes
- cell proliferation
- dna binding
- structure activity relationship
- binding protein
- cell death
- squamous cell carcinoma
- photodynamic therapy
- pi k akt
- weight loss
- data analysis
- insulin resistance
- squamous cell
- lymph node metastasis