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

任务单标题：用于预防结肠炎相关结直肠癌的下一代 GP130/IL-6/STAT3 抑制剂

• 批准号: 10627413
• 负责人: MARGIE CLAPPER
• 金额: $ 123.54万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-18 至 2024-11-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10627413
• 关键词: Animal Model; Binding; Biological Markers; Clinical; Colitis; Colitis associated colorectal cancer; Collaborations; Colorectal; Colorectal Cancer; Dangerousness; Disease; Dose; Drug Kinetics; Drug Targeting; Dysplasia; Early Intervention; Exhibits; Family; Generations; Goals; Growth Factor; IL6ST gene; Inflammation; Inflammation Mediators; Inflammatory; Interleukin 6 Receptor; Interleukin-6; Interleukins; Leukocyte Trafficking; Ligand Binding; Ligands; Link; Long-Term Effects; Malignant Neoplasms; Mediating; Mediator of activation protein; Membrane; Metabolic; Modeling; NF-kappa B; Oral; Oral Administration; Parents; Prevention; Process; Property; Regimen; Regulation; Role; STAT3 gene; Series; Signal Pathway; Signal Transduction; Solubility; Testing; Therapeutic; Toxic effect; Water; acquired immunity; adaptive immunity; analog; angiogenesis; chemokine; clinical development; cytokine; glycoprotein 130; improved; in vivo; inhibitor; insight; leukocyte activation; metastatic process; next generation; novel; pharmacodynamic biomarker; pre-clinical; preclinical study; prevent; receptor binding; small molecule inhibitor; targeted cancer therapy; tumor; tumor growth; tumorigenesis

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.

炎症介质是结肠炎相关性结直肠癌（CRC）的主要贡献者，并代表了早期干预的新靶点。在这些介质中，由于IL-6和STAT 3在肿瘤发生中的关键作用，特别是在涉及炎症的肿瘤如CRC中，GP 130/IL-6/STAT 3信号传导已被广泛研究[1]。IL-6通过与两种膜结合受体IL-6 R β和IL-6 R β（gp 130）结合来介导其作用[2]。配体结合诱导GP 130与IL-6 R β的结合，随后激活其下游信号传导途径，导致STAT-3的激活[3-5]、趋化因子指导的白细胞运输，以及通过调节白细胞活化、分化和增殖从先天性免疫向适应性免疫的转变[6]。STAT 3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可以与GP 130信号传导相关[7，8]。目前，没有GP 130的小分子抑制剂在临床开发中。 先前的研究将SC 144确定为GP 130的一流、有效、安全和口服活性抑制剂[3]。SC 144选择性地抑制由GP 130配体诱导的下游信号通路的激活。然而，SC 144表现出较差的溶解性和代谢不稳定性，这阻碍了该药剂的临床开发。最近，一系列的第二代SC 144类似物已被确定为口服活性，水溶性，并显示出理想的药代动力学（PK）特性，适用于先进的临床前研究。 该项目的总体目标是确定口服新一代GP 130/IL-6/STAT 3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的结直肠癌（CRC）。新发现的SC 144的水溶性类似物，具有改善的PK特性，应在发展结肠炎相关异型增生和癌症的结直肠炎症模型中测试抗肿瘤活性。应该评估SC 144类似物抑制肿瘤形成和调节相关生物标志物的能力。 参考文献： 1. 琼斯公司，舍勒，罗斯-约翰·S临床阻断IL-6/gp 130信号传导的治疗策略。J Clin Invest 121：3375-3383，2011. 2. 洪S. S.等人，A novel small-molecule inhibitor targeting the IL-6 receptor β subunit，glycoprotein 130. J Immunol 195：237-245，2015. 3. 徐S，内马提河gp 130：一个有希望的肿瘤治疗药物靶点。Expert Opin Ther Targets 17：1303-1328，2013. 4. 琼斯公司，Jenkins B. J.针对炎症性疾病和癌症中IL-6细胞因子家族的最新见解。Nat Rev Immunol 18：773-789，2018。 5. Taher M.Y.，Davies D.M.，Maher J.白细胞介素（IL）-6/IL-6受体轴在癌症中的作用。Biochem Soc Trans 46：1449-1462，2018。 6. Jones S.A.指导从先天性免疫到获得性免疫的转变：定义IL-6的作用。J Immunol 175：3463-3468，2005. 7. 约翰逊，O'Keefe R.A.，格兰迪斯JR靶向癌症中的IL-6/JAK/STAT 3信号传导轴。Nat Rev Clin Oncol 15：234-248，2018. 8. Grivennikov S.I.，卡琳·M危险的联系：STAT 3和NF-kappaB在癌症中的协作和串扰。细胞因子生长因子Rev 21：11-19，2010. 先前的研究将SC 144确定为GP 130的一流、有效、安全和口服活性抑制剂[3]。SC 144选择性地抑制由GP 130配体诱导的下游信号通路的激活。然而，SC 144表现出较差的溶解性和代谢不稳定性，这阻碍了该药剂的临床开发。最近，一系列的第二代SC 144类似物已被确定为口服活性，水溶性，并显示出理想的药代动力学（PK）特性，适用于先进的临床前研究。 该项目的总体目标是确定口服新一代GP 130/IL-6/STAT 3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的结直肠癌（CRC）。新发现的SC 144的水溶性类似物，具有改善的PK特性，应在发展结肠炎相关异型增生和癌症的结直肠炎症模型中测试抗肿瘤活性。应该评估SC 144类似物抑制肿瘤形成和调节相关生物标志物的能力。