1. Academic Validation
  2. Design, synthesis and biological evaluation of indole-2-one derivatives as potent BRD4 inhibitors

Design, synthesis and biological evaluation of indole-2-one derivatives as potent BRD4 inhibitors

  • Eur J Med Chem. 2020 Dec 15;208:112780. doi: 10.1016/j.ejmech.2020.112780.
Yu Xu 1 Xiu-Juan Zhang 1 Wen-Bo Li 1 Xing-Rong Wang 1 Shuai Wang 1 Xue-Peng Qiao 1 Shi-Wu Chen 2
Affiliations

Affiliations

  • 1 School of Pharmacy, Lanzhou University, Lanzhou, 730000, China.
  • 2 School of Pharmacy, Lanzhou University, Lanzhou, 730000, China. Electronic address: chenshw@lzu.edu.cn.
Abstract

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.

Keywords

BRD4; Cell-cycle; Indole-2-one; Scaffold hopping; c-Myc.

Figures
Products