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Eur J Med Chem. 2014 May 6;78:431-41. doi: 10.1016/j.ejmech.2014.03.065. Epub 2014 Mar 22.

Discovery of 2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide derivatives as new RORγ inhibitors using virtual screening, synthesis and biological evaluation.

Author information

1
Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou Science Park, Guangzhou, Guangdong 510530, China.
2
Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou Science Park, Guangzhou, Guangdong 510530, China; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenhe District, Shenyang, Liaoning 110016, China.
3
Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou Science Park, Guangzhou, Guangdong 510530, China; Department of Bioengineering, School of Pharmaceutical Sciences, Jilin University, No. 1266 Fujin Road, Chaoyang District, Changchun, Jilin 130021, China.
4
Department of Bioengineering, School of Pharmaceutical Sciences, Jilin University, No. 1266 Fujin Road, Chaoyang District, Changchun, Jilin 130021, China.
5
School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenhe District, Shenyang, Liaoning 110016, China.
6
Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou Science Park, Guangzhou, Guangdong 510530, China. Electronic address: xu_yong@gibh.ac.cn.

Abstract

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 IC50 values of 40-140 nM. These results represent a promising starting point for developing potent small molecule RORγ inhibitors.

KEYWORDS:

Nuclear hormone receptor; RORγ inhibitor; Th17 cell differentiation; Virtual screening

PMID:
24704616
DOI:
10.1016/j.ejmech.2014.03.065
[Indexed for MEDLINE]
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