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 smallmolecule 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);

A Novel Small-Molecule Inhibitor Targeting the IL-6 Receptor β Subunit, Glycoprotein 130

“…Moreover, madindoline A is produced in very low yield in microbial fermentation and is difficult to synthesize chemically. SC144 inhibits STAT3 signaling and suppresses ovarian cancer cells (31). However, in contrast with LMT-28, SC144 induces gp130 phosphorylation, and physical interaction between SC144 and gp130 has not yet been demonstrated.…”

“…Oxazolidinone derivatives are structurally related to biologically important bases and constitute a class of heterocyclic compounds that exhibit excellent druggability and substantial therapeutic activities, including antibiotic functions (34). Two small-molecule gp130 inhibitors, madindoline A (28,35) and SC144 (31), have been reported. The natural compound madindoline A inhibits IL-6 activity in vitro and inhibits bone resorption in vivo (28), and appears to bind to the extracellular domain of gp130 (35).…”

“…This negative effect was found to be dependent on the activation of MAPKs and de novo transcription and protein synthesis (19,27). Recently, the discovery of a small-molecule inhibitor of gp130 (SC144) for the treatment of ovarian cancer was reported (31), but an evidence of direct interaction between SC144 and gp130 was still missing.…”

Drug-induced modulation of gp130 signalling prevents articular cartilage degeneration and promotes repair

“…To evaluate this, we incubated pig articular chondrocytes with inhibitors of various proteins in this pathway in the presence of either LIF, a canonical activator of gp130, or RCGD 423 (figure 4A,B) and measured levels of pSTAT3 and MYC. Inhibitors of both JAKs and gp130 (SC144)35 greatly reduced pSTAT3 and MYC activation induced by both LIF and RCGD 423, while the compound induced gp130 activation in a dose-dependent manner (figure 4C), suggesting that RCGD 423 may directly interact with gp130 to induce signalling in the absence of ligand.…”

SPECT imaging of interleukin-6 receptor in ovarian tumor xenografts with a novel radiotracer of 99mTc-HYNIC-Aca-LSLITRL

“…Several molecular drugs were under clinical trials: siltuximab for inhibition IL-6, tocilizumab for inhibition IL-6 receptor and CDDO-Me targeting Stat3, etc. Meanwhile, a series of new drugs were developed and under the investigation (Ataie- Kachoie et al 2013;Xu et al 2013;He et al 2014). However, almost none of parameters provide an objective and early analysis of a therapeutic effect for above IL-6/IL-6R pathway targeting drugs.…”