Abstract 4598: GP130 as a novel therapeutic target in il-6-dependent cancers

Abstract The IL-6/GP130 signaling pathway is critical for the survival and progression of cancer cells of multiple cancer types. We report here the new discovery of Raloxifene (Marketed as Evista by Eli Lilly and Company) and Bazedoxifene [Marketed as Duavee (conjugated estrogens / bazedoxifene) by Pfizer] as novel inhibitors of IL-6/GP130 protein-protein interactions using multiple ligand simultaneous docking and drug repositioning approaches. Multiple drug scaffolds were simultaneously docked into binding hot spots of GP130 D1 domain by multiple ligand simultaneous docking to compete with the key interacting residues of IL-6, followed by tethering to generate virtual hit compounds. Similarity searches of virtual hits on drug databases identified Raloxifene and Bazedoxifene as potential inhibitors of IL-6/GP130 interaction. Both Raloxifene and Bazedoxifene are known as selective estrogen receptor modulators and we identified their novel function as GP130 inhibitors. Raloxifene and Bazedoxifene inhibited IL-6 mediated induction of STAT3 phosphorylation in cancer cells, which confirm their ability to inhibit IL-6/GP130 signaling. In contrast, Raloxifene and Bazedoxifene did not inhibit the induction of STAT1 phosphorylation by IFN-γ in cancer cells indicating their selectivity. Raloxifene and Bazedoxifene also inhibited STAT3 phosphorylation and resulted in apoptosis in cancer cells expressing elevated IL-6 levels. In addition, addition of excess IL-6 reversed the expression level of STAT3 phosphorylation which was decreased by Raloxifene or Bazedoxifene supporting that both FDA-approved drugs act through IL-6/GP130 signaling. Compared with an original GP130 inhibitor MDL-A whose IC50 values were 108-216 µM in cancer cell lines, Raloxifene and Bazedoxifene were found more potent in inhibiting cell viability which the IC50 values for Raloxifene and Bazedoxifene were 6.9-8.9 µM and 3.4-4.4 µM respectively in the same cancer cell lines expressing elevated IL-6 levels. Furthermore, both Raloxifene and Bazedoxifene significantly suppressed the tumor growth of human RH30 sarcoma cells in mouse xenograft model in vivo. These findings suggest that FDA-approved drugs Raloxifene and Bazedoxifene may serve as novel GP130-targeting therapeutic drugs in IL-6 dependent cancers. Citation Format: Hui Xiao, Yang Bian, Chengguang Zhao, Li Lin, David Jou, Huameng Li, Chenglong Li, Jiayuh Lin. GP130 as a novel therapeutic target in il-6-dependent cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4598. doi:10.1158/1538-7445.AM2014-4598