Supplementary Figures 1 - 8 from Discovery of a Novel Orally Active Small-Molecule gp130 Inhibitor for the Treatment of Ovarian Cancer

Xu, Shili; Grande, Fedora; Garofalo, Antonio; Neamati, Nouri

doi:10.1158/1535-7163.22501387.v1

15357163mct121082-sup-fig1-8.pdf (1.22 MB)

Supplementary Figures 1 - 8 from Discovery of a Novel Orally Active Small-Molecule gp130 Inhibitor for the Treatment of Ovarian Cancer

journal contribution

posted on 2023-04-03, 14:13 authored by Shili Xu, Fedora Grande, Antonio Garofalo, Nouri Neamati

PDF file - 1250K, Supplementary Figure S1: SC144 exhibits cytotoxicity in human ovarian cancer cell lines; Supplementary Figure S2: Confirmation of gp130 protein expression, glycosylation phosphorylation and internalization; Supplementary Figure S3: Constitutive Stat3 (Tyr705) phosphorylation is gp130 dependent; Supplementary Figure S4: gp130/Stat3 knockdown suppresses the expression of downstream genes; Supplementary Figure S5: SC144's effects on pancreatic cancer cells; Supplementary Figure S6: Gp130/Stat3 inhibition causes cytotoxicity in ovarian cancer cells; Supplementary Figure S7: SC144 inhibits cytokine-induced Stat3 activation; Supplementary Figure S8: SC144 treatment did not cause systemic toxicity.

History

ARTICLE 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 drug target in ovarian cancer due to its role in promoting cancer progression via the activation of its downstream Stat3 signaling. We also present preclinical studies of SC144, the first-in-class orally active small-molecule gp130 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 tumor growth in a mouse xenograft model of human ovarian cancer without significant toxicity to normal tissues. Mol Cancer Ther; 12(6); 937–49. ©2013 AACR.