Discovery of a Novel Orally Active Small-Molecule gp130 Inhibitor for the Treatment of Ovarian Cancer
作者： Shili Xu , Fedora Grande , Antonio Garofalo , Nouri Neamati
DOI: 10.1158/1535-7163.MCT-12-1082
关键词: Ovarian cancer 、 Glycoprotein 130 、 Cell culture 、 STAT3 、 Regulation of gene expression 、 Phosphorylation 、 Cancer 、 Interleukin 、 Pharmacology 、 Biology
摘要: Interleukin (IL)-6 and Stat3 play key roles in ovarian cancer progression. However, the role of glycoprotein 130 (gp130), signal transducer this signaling axis, is not well-established. Currently, there are no small-molecule inhibitors gp130 under clinical development. In study, we show that an attractive drug target due to its promoting progression via activation downstream signaling. We also present preclinical studies SC144, first-in-class orally active inhibitor. SC144 shows greater potency human cell lines than normal epithelial cells. binds gp130, induces phosphorylation (S782) deglycosylation, abrogates nuclear translocation, further inhibits expression genes. addition, potent inhibition ligand-triggered Oral administration delays tumor growth a mouse xenograft model without significant toxicity tissues.
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