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FL-411 is a potent and selective BRD4 inhibitor with an IC50 of 0.43±0.09 μM for BRD4(1).

FL-411 is a selective BRD4 inhibitor. Binding affinities of FL-411 are measured by TR-FRET against the first and second bromodomains of BRD2(1), BRD4(1), and BRD4(2) with IC50s of 24.60±0.70 μM, 0.47±0.02 μM, 0.93±0.05 μM, respectively. FL-411 possesses a good BRD4(1) inhibition activity (IC50=0.43±0.09 μM), antiproliferative activity (MCF-7, IC50=1.62±0.06 μM; MDA-MB-231, IC50=3.27±0.14 μM), and autophagic activity (42.29% in MCF-7 cells), as well as displays a low toxicity against MCF10A cells). FL-411 induces ATG5-dependent autophagy-associated cell death (ACD) by blocking BRD4-AMPK interaction and thus activating AMPK-mTOR-ULK1-modulated autophagic pathway in breast cancer cells[1].

To evaluate the antitumor activity of FL-411 in vivo, two breast tumor xenograft models, namely, MCF-7 and MDA-MB-231 cell lines models, are used. The in vivo study is conducted using three different doses of FL-411: 25 mg/kg, 50 mg/kg, and 100 mg/kg. In all the models, FL-411 shows significant tumor growth inhibition in a dose-dependent manner as determined by 80% and 76% tumor growth inhibition ratio in MCF-7 and MDA-MB-231 cell models, respectively. A remarkable loss of tumor weights is observed in all dose groups (p<0.001). FL-411 displays no obvious effects on the body weight of all the treatment groups. To examine whether FL-411-mediated inhibition of tumor growth in vivo is associated with reduced cell proliferation and the increased autophagy-associated cell death, tumor tissues from control and FL-411-treated mice are processed for the immunohistochemical analysis of Ki-67 and LC3. FL-411 treatment obviously reduces the number of Ki-67 (p<0.001) positive cells as well as increases autophagy levels, which is determined by increased LC3 expression (p<0.001)[1].

[1]. Ouyang L, et al. Discovery of a Small-Molecule Bromodomain-Containing Protein 4 (BRD4) Inhibitor That InducesAMP-Activated Protein Kinase-Modulated Autophagy-Associated Cell Death in Breast Cancer. J Med Chem. 2017 Dec 28;60(24):9990-10012

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