title: Discovery of a novel orally active small-molecule gp130 inhibitor for the treatment of ovarian cancer.
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.
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Shili
authors.initials: S
authors.lastname: Xu
authors.forename: Fedora
authors.initials: F
authors.lastname: Grande
authors.forename: Antonio
authors.initials: A
authors.lastname: Garofalo
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
mesh_terms: D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D063646:Carcinogenesis / Q000187:drug effects*; D045744:Cell Line, Tumor; D050822:Cytokine Receptor gp130 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage*; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation; D011810:Quinoxalines / Q000008:administration & dosage*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D006834:Hydrazines; C494199:IL6ST protein, human; D015850:Interleukin-6; C544427:N'-(7-fluoroH-pyrrolo(1,2-a)quinoxalin-4-yl)pyrazine-2-carbohydrazide; D011810:Quinoxalines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050822:Cytokine Receptor gp130