Discovery of 2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide derivatives as new RORγ inhibitors using virtual screening, synthesis and biological evaluation.
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.
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.
Yan
Y
Zhang
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.
Xiaoqian
X
Xue
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.
Xiangyu
X
Jin
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.
Yu
Y
Song
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.
Jing
J
Li
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.
Xiaoyu
X
Luo
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.
Ming
M
Song
Department of Bioengineering, School of Pharmaceutical Sciences, Jilin University, No. 1266 Fujin Road, Chaoyang District, Changchun, Jilin 130021, China.
Weiqun
W
Yan
School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenhe District, Shenyang, Liaoning 110016, China.
Hongrui
H
Song
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.
Yong
Y
Xu
D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D057166:High-Throughput Screening Assays; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D007211:Indoles; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D013449:Sulfonamides
Nuclear hormone receptor; RORγ inhibitor; Th17 cell differentiation; Virtual screening