Interleukin (IL)-6 and Stat3 play key roles in ovarian cancer progression. However, the role of glycoprotein 130 (gp130), the signal transducer of this signaling axis, is not well-established. Currently, there are no small-molecule inhibitors of gp130 under clinical development. In this study,we show that gp130 is an attractive drugtarget in ovarian cancer due to its role in promoting cancer progression via the activation of its downstream11 Stat3 signaling. We also present preclinical studies of SC144, the first-in-class orally active small-moleculegp130 inhibitor. SC144 shows greater potency in human ovarian cancer cell lines than in normal epithelial cells.SC144 binds gp130, induces gp130 phosphorylation (S782) and deglycosylation, abrogates Stat3 phosphorylation and nuclear translocation, and further inhibits the expression of downstream target genes. In addition,SC144 shows potent inhibition of gp130 ligand–triggered signaling. Oral administration of SC144 delays tumorgrowth in a mouse xenograft model of human ovarian cancer without significant toxicity to normal tissues.

Discovery of a novel orally active small-molecule gp130 inhibitor for the treatment of ovarian cancer

GRANDE, Fedora;GAROFALO, Antonio;
2013-01-01

Abstract

Interleukin (IL)-6 and Stat3 play key roles in ovarian cancer progression. However, the role of glycoprotein 130 (gp130), the signal transducer of this signaling axis, is not well-established. Currently, there are no small-molecule inhibitors of gp130 under clinical development. In this study,we show that gp130 is an attractive drugtarget in ovarian cancer due to its role in promoting cancer progression via the activation of its downstream11 Stat3 signaling. We also present preclinical studies of SC144, the first-in-class orally active small-moleculegp130 inhibitor. SC144 shows greater potency in human ovarian cancer cell lines than in normal epithelial cells.SC144 binds gp130, induces gp130 phosphorylation (S782) and deglycosylation, abrogates Stat3 phosphorylation and nuclear translocation, and further inhibits the expression of downstream target genes. In addition,SC144 shows potent inhibition of gp130 ligand–triggered signaling. Oral administration of SC144 delays tumorgrowth in a mouse xenograft model of human ovarian cancer without significant toxicity to normal tissues.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11770/139620
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