1608127-95-2Relevant academic research and scientific papers
Discovery of Benzo[cd]indol-2(1H)-ones as Potent and Specific BET Bromodomain Inhibitors: Structure-Based Virtual Screening, Optimization, and Biological Evaluation
Xue, Xiaoqian,Zhang, Yan,Liu, Zhaoxuan,Song, Ming,Xing, Yanli,Xiang, Qiuping,Wang, Zhen,Tu, Zhengchao,Zhou, Yulai,Ding, Ke,Xu, Yong
, p. 1565 - 1579 (2016/03/05)
The discovery of inhibitors of bromodomain and extra terminal domain (BET) has achieved great progress, and at least seven inhibitors have progressed into clinical trials for the treatment of cancer or inflammatory diseases. Here, we describe the identification, optimization, and evaluation of benzo[cd]indol-2(1H)-one containing compounds as a new class of BET bromodomain inhibitors, starting from structure-based virtual screening (SBVS). Through structure-based optimization, potent compounds were obtained with significantly improved activity. The two most potent compounds bind to the BRD4 bromodomain, with Kd values of 124 and 137 nM. Selected compounds exhibited high selectivity over other non-BET subfamily members. Notably, compound 85 demonstrated a reasonable antiproliferation effect on MV4;11 leukemia cells and exhibited a good pharmacokinetic profile with high oral bioavailability (75.8%) and moderate half-life (T1/2 = 3.95 h). The resulting lead molecule 85 represents a new, potent, and selective class of BET bromodomain inhibitors for the development of therapeutics to treat cancer and inflammatory diseases.
Discovery of 2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide derivatives as new RORγ inhibitors using virtual screening, synthesis and biological evaluation
Zhang, Yan,Xue, Xiaoqian,Jin, Xiangyu,Song, Yu,Li, Jing,Luo, Xiaoyu,Song, Ming,Yan, Weiqun,Song, Hongrui,Xu, Yong
, p. 431 - 441 (2014/04/17)
Retinoic acid receptor-related orphan receptor γ (RORγ), a member of the nuclear hormone receptor superfamily, is a promising therapeutic target for treating Th17-mediated autoimmune diseases. We performed structure-based virtual screening targeting the RORγ ligand-binding domain. Among the tested compounds, s4 demonstrated RORγ antagonistic activities with micromolar IC50 values in both an AlphaScreen assay (20.27 μM) and a cell-based reporter gene assay (11.84 μM). Optimization of the s4 compound led to the identification of compounds 7j, 8c, 8k, and 8p, all of which displayed significantly enhanced RORγ inhibition with IC 50 values of 40-140 nM. These results represent a promising starting point for developing potent small molecule RORγ inhibitors.
