LAUSR

Bromodomain protein 4 (BRD4) plays a crucial role in transcriptional regulation and is considered to be a viable drug target for cancer treatment. Herein, we designed and synthesized a series of indole-2-one derivatives through scaffold hopping drug design. Most of the compounds showed potent BRD4 inhibitory activities and anti-proliferation activities in cancer cell lines. Especially, compound 12j exhibited excellent BRD4 inhibitory activities (BD1 IC50 = 19 nM, BD2 IC50 = 28 nM) and anti-proliferation potency with IC50 values of 4.75 μM and 1.35 μM in HT-29 and HL-60 cells, respectively. Additionally, docking studies showed that the hydrophobic pocket next to KAc region and WPF shelf were critical to the activity of the compound. Compound 12j could arrest the cell-cycle progression of HT-29 cells into the G1 phase and reduce the expression of c-Myc. Moreover, compound 12j exhibited favorable oral pharmacokinetic properties. All the results demonstrated that compound 12j was a potent BRD4 inhibitor and had merely potential for colon cancer treatment.