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Relevant academic research and scientific papers

Design, synthesis and biological evaluation of dihydroquinoxalinone derivatives as BRD4 inhibitors

BRD4 plays a key role in transcriptional regulation. Recent biological and pharmacological studies have demonstrated that bromodomain-containing protein 4 (BRD4) is a viable drug target for cancer treatment. In this study, we synthesized a series of dihydroquinoxalinone derivatives and evaluated their BRD4 inhibitory activities, obtaining compound 5i with IC50 value of 73?nM of binding activity in BRD4(1) and 258?nM of cellular activity in MV-4-11 cancer cell lines. Docking studies were performed to explain the structure-activity relationship. Based on its potent biochemical and anti-proliferative activity, the novel BRD4 inhibitor compound 5i, is a promising lead compound for further investigation.

Iron- or Zinc-Mediated Synthetic Approach to Enantiopure Dihydroquinoxalinones

A general and efficient synthesis of enantiopure dihydroquinoxalinones has been developed using naturally occurring amino acids as starting materials. The reductive cyclization of N-(o-nitroaryl)amino esters was performed by using iron and zinc metal under mild conditions in a water/ethyl acetate mixture. The corresponding dihydroquinoxalinones were obtained in moderate to high yields and high enantiomeric purity, among which 7 new compounds were unprecedented in the literature.

Discovery of a series of dihydroquinoxalin-2(1H)-ones as selective BET inhibitors from a dual PLK1-BRD4 inhibitor

Recent years have seen much effort to discover new chemotypes of BRD4 inhibitors. Interestingly, some kinase inhibitors have been demonstrated to be potent bromodomain inhibitors, especially the PLK1 inhibitor BI-2536 and the JAK2 inhibitor TG101209, which can bind to BRD4 with IC50 values of 0.025 μM and 0.13 μM, respectively. Although the concept of dual inhibition is intriguing, selective BRD4 inhibitors are preferred as they may diminish off-target effects and provide more flexibility in anticancer drug combination therapy. Inspired by BI-2536, we designed and prepared a series of dihydroquinoxalin-2(1H)-one derivatives as selective bromodomain inhibitors. We found compound 54 had slightly higher activity than (+)-JQ1 in the fluorescence anisotropy assay and potent antiproliferative cellular activity in the MM.1S cell line. We have successfully solved the cocrystal structure of 52 in complex with BRD4-BD1, providing a solid structural basis for the binding mode of compounds of this series. Compound 54 exhibited high selectivity over most non-BET subfamily members and did not show bioactivity towards the PLK1 kinase at 10 or 1 μM. From in vivo studies, compound 54 demonstrated a good PK profile, and the results from in vivo pharmacological studies clearly showed the efficacy of 54 in the mouse MM.1S xenograft model.