Bromodomain-containing protein 4 (BRD4) belongs to the bromodomain and extra-terminal (BET) protein family, functions as an epigenetic and transcriptional regulatory. FL-411 shows potent inhibitory activity against BRD4 with an IC50 value of 0.43 µM. It also inhibited the proliferation of MCF-7 cells and MDA-MB-231 cells with IC50 values of 1.62 μM and 3.27 μM, respectively. In MCF-7 and MDA-MB-231 cells treated with 1.5 or 3 μM FL-411, the expression of BRD4 and its downstream target c-Myc were greatly inhibited as compared to the control group, whereas the phosphorylation of AMPKα at thr172 site was activated. FL-411 also augmented the interaction between p53 and AMPK, but attenuated the interaction between BRD4 and p53 in MCF-7 cells. FL-411 at 1.5 or 3 μM downregulated the expression levels of p-Akt (ser473), p-Akt (thr308), and p-mTOR (ser2448) in MCF-7 or MDA-MB-231 cells, while the expressions of Akt and mTOR remained unchanged. The administration of FL-411 (25, 50, and 100 mg/kg) resulted in 80% and 76% tumor growth inhibition in mice models inoculated with MCF-7 or MDA-MB-231 cells, respectively, in a dose-dependent manner. FL-411-treated animals also showed reduced number of Ki-67 positive cells and increased LC3 expression in the tumor tissues[1].
作用机制
FL-411 is a potent and selective inhibitor of BRD4. The 3,5-dimethylphenol moiety of FL-411 penetrated into the N-acetylated lysine pocket of the enzyme, forming a direct hydrogen bond. The residues Gln85 and Pro82 contribute to the selectivity of FL-411 over BRD4.
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