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

炎症介质是结肠炎相关性结直肠癌(CRC)的主要贡献者，是早期干预的新靶点。在这些介质中，gp130/IL-6/STAT3信号已被广泛研究，因为IL-6和STAT3在肿瘤发生中的关键作用，特别是在肿瘤的炎症，如结直肠癌[1]。IL-6通过与两种膜结合受体IL-6R和IL-6Rβ(Gp130)结合来介导其作用。配体结合诱导gp130与IL-6R结合，随后激活其下游信号通路，导致STAT-3[3-5]激活，趋化因子引导的白细胞运输，并通过调节白细胞的激活、分化和增殖从天然免疫转变为获得性免疫[6]。STAT3活性与肿瘤生长、存活、血管生成和转移过程相关；这些过程中的每一个都与gp130信号联系在一起[7，8]。目前，还没有小分子的gp130抑制剂处于临床开发阶段。 以前的研究证实SC144是一种一流的、有效、安全的gp130口服活性抑制剂[3]。SC144选择性地抑制gp130配体诱导的下游信号通路的激活。然而，SC144具有较差的溶解性和代谢不稳定性，这阻碍了该制剂的临床应用。最近，一系列第二代SC144类似物被确定为口服活性的，水溶性的，并显示出良好的药代动力学(PK)特性，适合于高级临床前研究。 该项目的总体目标是确定口服新一代gp130/IL-6/STAT3抑制剂是否可以在适当的临床前动物模型中抑制结肠炎相关性结直肠癌(CRC)。新发现的具有改善PK特性的SC144的水溶性类似物，应该在结肠炎相关的异型增生和癌症的结肠炎模型中进行抗肿瘤活性测试。应评估SC144类似物抑制肿瘤形成和调节相关生物标记物的能力。 参考资料： 1.Jones S.A.，Scheller J.，Rose-John S.临床阻断IL-6/gp130信号的治疗策略。J Clin Invest 121：3375-3383,2011。 2.洪善胜等人。一种针对IL-6受体β亚单位糖蛋白130的新型小分子抑制剂。J免疫杂志195：237-245,2015。 3.Neamati N.gp130：一种很有前途的癌症治疗药物靶点。专家Opin Ther的目标是，2013年17：1303-1328。 4.Jones S.A.，Jenkins B.J.在炎症性疾病和癌症中针对IL-6细胞因子家族的最新见解。NAT Rev免疫18：773-789,2018。 5.Taher M.Y.，Davies D.M.，Maher J.白介素6/白介素6受体轴在癌症中的作用。生物化学学报46：1449-1462,2018。 6.Jones S.A.指导从先天免疫到后天免疫的转变：定义IL-6的角色。免疫杂志175：3463-3468,2005。 7.Johnson D.E.，O‘Keefe R.A.，Granis J.R.针对癌症中的IL-6/JAK/STAT3信号轴。NAT Rev Clin Oncol15：234-248,2018。 8.Grivennikov S.I.，Karin M.危险联系：STAT3和NF-kappaB在癌症中的合作和串扰。细胞因子生长因子修订版21：11-19,2010。 以前的研究证实SC144是一种一流的、有效、安全的gp130口服活性抑制剂[3]。SC144选择性地抑制gp130配体诱导的下游信号通路的激活。然而，SC144具有较差的溶解性和代谢不稳定性，这阻碍了该制剂的临床应用。最近，一系列第二代SC144类似物被确定为口服活性的，水溶性的，并显示出良好的药代动力学(PK)特性，适合于高级临床前研究。 该项目的总体目标是确定口服新一代gp130/IL-6/STAT3抑制剂是否可以在适当的临床前动物模型中抑制结肠炎相关性结直肠癌(CRC)。新发现的具有改善PK特性的SC144的水溶性类似物，应该在结肠炎相关的异型增生和癌症的结肠炎模型中进行抗肿瘤活性测试。应评估SC144类似物抑制肿瘤形成和调节相关生物标记物的能力。

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.