Abstract IA003: SC144 and the next generation IL6/GP130/STAT3 inhibitors for cancer prevention


 IL6/GP130/STAT3 signaling plays a crucial role in multiple diseases, and all components of this signaling cascade are directly or indirectly implicated in tumorigenesis. Therefore, blockade of this signaling axis is expected to provide novel therapeutic opportunities to treat various diseases including cancer. IL6 binds to IL6R and GP130 to activate downstream signaling pathways to promote proliferation, survival and metastasis of cancer cells, and to stimulate angiogenesis on endothelial cells. Although GP130 is positioned at the junction of this oncogenic signaling network and is essential for activation of the network, there are no small-molecule inhibitors of GP130 under clinical development. Previously, we identified SC144 as a first-in-class, efficacious, safe, and orally active inhibitor of GP130. SC144 selectively inhibits the activation of downstream signaling pathways induced by GP130 ligands (IL6, LIF), with no significant effects on the activation by non-GP130 ligands, such as IFN-γ, SDF-1α, and PDGF. SC144 exhibits cytotoxicity in a panel of platinum-sensitive and platinum-resistant cells, with no significant cytotoxicity to human normal epithelial cells. In mouse xenograft models, SC144 significantly inhibited tumor growth through GP130 inhibition and induction of necrosis in the tumor. No toxicity was evident in normal tissues. Furthermore, SC144 showed significant in vivo efficacy in immune competent syngeneic mouse models. Unfortunately, clinical development of SC144 was delayed due to its poor solubility and metabolic instability. During the past two years, we have identified metabolic liabilities of SC144 and have undertaken an extensive medicinal chemistry lead optimization campaign to produce analogs with increased solubility and metabolic stability. The new analogs show favorable properties in single- and repeat-dosing pharmacokinetic (PK) studies. As a result, we have in hand a series of 2nd-generation analogs that are orally active, water-soluble, and display desirable PK properties suitable for advanced preclinical studies to support IND filing.
 Citation Format: Nouri Neamati. SC144 and the next generation IL6/GP130/STAT3 inhibitors for cancer prevention [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr IA003.