Synthesis and biological evaluation of indazole-4,7-dione derivatives as novel BRD4 inhibitors

doi:10.1007/s12272-017-0978-y

Paper

Synthesis and biological evaluation of indazole-4,7-dione derivatives as novel BRD4 inhibitors

Published Nov 4, 2017 · Minjin Yoo, Miyoun Yoo, J. Kim

Archives of Pharmacal Research

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4

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Abstract

Bromodomain-containing protein 4 (BRD4) is known to regulate the expression of c-Myc to control the proliferation of cancer cells. Therefore, development of small-molecule inhibitors targeting the bromodomain has been widely studied. However, some clinical trials on BRD4 inhibitors have shown its drawbacks such as toxicity including the loss of organ weight. Here, we report the development of the novel and promising scaffold, 1H-indazol-4,7-dione, as a bromodomain inhibitor and synthesized derivatives for the inhibition of binding of bromodomain to acetylated histone peptide. Through this effort, we obtained 6-chloro-5-((2,6-difluorophenyl)amino)-1H-indazole-4,7-dione (5i), which showed a highly potent activity with a half-maximal inhibitory concentration (IC50) of 60 nM. The in vivo xenograft assay confirmed that the 1H-indazol-4,7-dione compound reduced the tumor size significantly. These results show that the 1H-indazol-4,7-dione scaffold is highly potent against bromodomain.

In Vitro Study

Study Snapshot

The 1H-indazol-4,7-dione scaffold is highly potent against bromodomain, reducing tumor size and showing potential as a cancer drug.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

Synthesis and biological evaluation of indazole-4,7-dione derivatives as novel BRD4 inhibitors

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