Discovery of bazedoxifene analogues targeting glycoprotein 130.

Deregulation of GP130 in signal transduction is involved in multiple types of human diseases, especially in cancers, indicating that GP130 is an attractive target for cancer therapy. However, GP130 was conventionally considered as an undruggable target thus the discovery of GP130 PPI inhibitors is extremely challenging. By the aid of structure-based drug design, in this study, two series of bazedoxifene based analogues were designed to target GP130 D1 domain and block the IL-6/GP130/STAT3 signaling pathway for antitumor treatment. Most of these designed compounds displayed potent anti-proliferative activity against cancer cells. The representative compound 10a was demonstrated to directly bind to GP130 protein with an affinity (K D) value of 3.8 μM via both SPR and DARTS methods. Subsequently, molecular docking study predicted that 10a targeted D1 domain of GP130 and co-IP assay demonstrated that 10a did not inhibit IL-6R/GP130 interaction, which meant 10a did not bind to the D2 and D3 domains of GP130. Moreover, 10a selectively inhibited JAK2 and STAT3 phosphorylation as well as IL-6 induced STAT3 phosphorylation. 10a effectively inhibited tumor cell viability, migration and promoted apoptosis. Furthermore, 10a effectively suppressed xenograft model tumor growth in vivo. Taken together, this study described a new class of bazedoxifene derived GP130 inhibitors as antitumor agents. Compound 10a targets GP130 and inhibits the activation of JAK2/STAT3 pathway to exert antitumor activity. Image 1 • Novel bazedoxifene based analogues were designed as direct GP130 inhibitors for anti-cancer treatment. • 10a was indicated as a directly GP130 D1 domain inhibitor and blocked the IL-6/GP130/STAT3 signaling pathway. • 10a exhibited potent antitumor activity in vitro. • 10a arrested tumor growth in vivo. [ABSTRACT FROM AUTHOR]