TASK ORDER TITLE: NEXT GENERATION GP130/IL-6/STAT3 INHIBITORS FOR THE PREVENTION OF COLITIS-ASSOCIATED COLORECTAL CANCER

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Inflammatory mediators are major contributors to colitis-associated colorectal cancer (CRC), and represent novel targets for early intervention. Among these mediators, GP130/IL-6/STAT3 signaling has been widely studied due to the critical roles of IL-6 and STAT3 in tumorigenesis, especially in tumors involving inflammation such as CRC [1]. IL-6 mediates its effects by binding to two membrane bound receptors, IL-6R and IL-6Rβ (gp130) [2]. Ligand binding induces the association of GP130 with IL-6R, followed by activation of its downstream signaling pathway leading to activation of STAT-3 [3-5], chemokine-directed leukocyte trafficking, and the transition from innate to adaptive immunity via regulation of leukocyte activation, differentiation, and proliferation [6]. STAT3 activity correlates with tumor growth, survival, angiogenesis, and metastatic processes; each of these processes can be linked to GP130 signaling [7,8]. Currently, there are no small-molecule inhibitors of GP130 under clinical development. Previous studies identified SC144 as a first-in-class, efficacious, safe, and orally active inhibitor of GP130 [3]. SC144 selectively inhibits the activation of downstream signaling pathways induced by GP130 ligands. However, SC144 exhibits poor solubility and metabolic instability, which has prevented clinical development of this agent. Recently, a series of second-generation SC144 analogs have been identified that are orally active, water-soluble, and display desirable pharmacokinetic (PK) properties suitable for advanced preclinical studies. The overall goal of this project is to determine if oral administration of newer generation GP130/IL-6/STAT3 inhibitors can inhibit colitis-associated colorectal cancer (CRC) in appropriate pre-clinical animal models. Newly identified water-soluble analogues of SC144, with improved PK properties, should be tested for anti-tumor activity in models of colorectal inflammation that develop colitis-associated dysplasia and cancers. The SC144 analogues should be evaluated for their ability to inhibit tumor formation and modulate associated biomarkers. References: 1. Jones S.A., Scheller J., Rose-John S. Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J Clin Invest 121:3375-3383, 2011. 2. Hong S.-S. et al. A novel small-molecule inhibitor targeting the IL-6 receptors β subunit, glycoprotein 130. J Immunol 195: 237-245, 2015. 3. Xu S., Neamati N. gp130: a promising drug target for cancer therapy. Expert Opin Ther Targets 17:1303-1328, 2013. 4. Jones S.A., Jenkins B.J. Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer. Nat Rev Immunol 18:773-789, 2018. 5. Taher M.Y., Davies D.M., Maher J. The role of the interleukin (IL)-6/IL-6 receptor axis in cancer. Biochem Soc Trans 46:1449-1462, 2018. 6. Jones S.A. Directing transition from innate to acquired immunity: defining a role for IL-6. J Immunol 175:3463-3468, 2005. 7. Johnson D.E., O'Keefe R.A., Grandis J.R. Targeting the IL-6/JAK/STAT3 signaling axis in cancer. Nat Rev Clin Oncol 15: 234-248, 2018. 8. Grivennikov S.I., Karin M. Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev 21:11-19, 2010. Previous studies identified SC144 as a first-in-class, efficacious, safe, and orally active inhibitor of GP130 [3]. SC144 selectively inhibits the activation of downstream signaling pathways induced by GP130 ligands. However, SC144 exhibits poor solubility and metabolic instability, which has prevented clinical development of this agent. Recently, a series of second-generation SC144 analogs have been identified that are orally active, water-soluble, and display desirable pharmacokinetic (PK) properties suitable for advanced preclinical studies. The overall goal of this project is to determine if oral administration of newer generation GP130/IL-6/STAT3 inhibitors can inhibit colitis-associated colorectal cancer (CRC) in appropriate pre-clinical animal models. Newly identified water-soluble analogues of SC144, with improved PK properties, should be tested for anti-tumor activity in models of colorectal inflammation that develop colitis-associated dysplasia and cancers. The SC144 analogues should be evaluated for their ability to inhibit tumor formation and modulate associated biomarkers.