Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA.
Mol Cancer Ther. 2013 Jun;12(6):937-49. doi: 10.1158/1535-7163.MCT-12-1082. Epub 2013 Mar 27.
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.
白细胞介素 (IL)-6 和 Stat3 在卵巢癌进展中发挥关键作用。然而，该信号通路的信号转导器糖蛋白 130 (gp130) 的作用尚未得到充分证实。目前，临床上没有针对 gp130 的小分子抑制剂。在这项研究中，我们表明 gp130 是卵巢癌中有吸引力的药物靶点，因为它通过激活其下游 Stat3 信号促进癌症进展。我们还介绍了 gp130 的第一个口服活性小分子抑制剂 SC144 的临床前研究。SC144 在人卵巢癌细胞系中的活性大于正常上皮细胞。SC144 结合 gp130，诱导 gp130 磷酸化 (S782) 和去糖基化，阻断 Stat3 磷酸化和核转位，并进一步抑制下游靶基因的表达。此外，SC144 对 gp130 配体触发的信号具有很强的抑制作用。SC144 的口服给药可延迟人卵巢癌小鼠异种移植模型中的肿瘤生长，而对正常组织无明显毒性。
