FL-411

Research use only, not for human use.

FL-411 is a novel small-molecule inhibitor of BRD4.

FL-411 is a novel small-molecule inhibitor of BRD4, induces ATG5-dependent autophagy-associated cell death (ACD) by blocking BRD4-AMPK interaction and activating AMPK-mTOR-ULK1-modulated autophagic pathway in breast cancer cells; induces ACD pathways involved in HMGB1, VDAC1/2, and eEF2, displays a therapeutic potential on both breast cancer xenograft mouse and zebrafish models.

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.

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).

FL411

Chromatin/Epigenetic

Bromodomain

BRD4

Cancer

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2118944-88-8

341.429

C18H19N3O2S

>98% (HPLC)

< 1 mg/ml refers to the product slightly soluble or insoluble

CC1=CC(=CC(=C1O)C)C2=NC3=C(C4=C(S3)CN(CC4)C)C(=O)N2

2-(4-Hydroxy-3,5-dimethylphenyl)-7-methyl-5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one

(-20℃)

With Ice Pack

≥ 2 years