Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 29, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2020.115857
Keywords
BRD4 inhibitors; Pancreatic cancer; Molecular docking; Antitumor
Funding
- Natural Science Foundation of Jiangsu Province [BK 20141349]
- China National Key HiTech Innovation Project for the R&D of Novel Drugs [2013ZX09301303-002]
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BRD4 inhibitor HB100-A7 showed excellent inhibitory activities against BRD4 protein in vitro, suppressing pancreatic cancer cell proliferation and inducing apoptosis. In vivo study further confirmed its significant tumor growth inhibition effect in a pancreatic mouse tumor model, suggesting its potential as a promising lead compound for further development as a new generation of small molecule inhibitors targeting BRD4.
Bromodomain containing protein 4 (BRD4) has been demonstrated to play critical roles in cellular proliferation and cell cycle progression. In this study, using the BRD4 inhibitor Fragment 9 as a lead compound, a series of imidazolopyridone derivatives were designed and tested for their inhibitory activity against BRD4 protein in vitro. Among them, HB100-A7 showed excellent BRD4(1) inhibitory activities with an IC50 value of 0.035 mu M in amplified luminescent proximity homogeneous assay (Alphascreen). The result of MTT assay showed that HB100-A7 could suppress the proliferation of pancreatic cancer cells. In addition, flow cytometry further illustrated that HB100-A7 treatment resulted in G0/G1 phase arrest and promoted apoptosis of BxPc3 cells. Furthermore, the in vivo study found that HB100-A7 displayed significant tumor growth inhibition in a pancreatic mouse tumor model (Panc-02). Moreover, IHC staining suggested that HB100-A7 induce cell apoptosis in pancreatic cancer tumor tissue. Together, this study revealed, for the first time, HB100-A7 is a promising lead compound for further development as a new generation of small molecule inhibitors targeting the BRD4 protein.
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