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结直肠癌 (CRC) 的主要促成因素，并且是早期干预的新靶点，其中 GP130/IL-6/STAT3 信号传导由于 IL-6 和 STAT3 的关键作用而得到了广泛研究。 IL-6 通过与两种膜结合受体 IL-6Rα 和 IL-6Rβ 结合来介导其作用。 (gp130) [2] 诱导 GP130 与 IL-6Rα 结合，随后激活其下游信号通路，从而激活 STAT-3 [3-5]、趋化因子引导的白细胞运输和转变。通过调节白细胞活化、分化和增殖从先天免疫到适应性免疫[6]。与 GP130 信号传导有关 [7,8] 目前，尚无 GP130 的小分子抑制剂正在临床开发中。 先前的研究发现 SC144 是一种首创、有效、安全且具有口服活性的 GP130 抑制剂 [3]，它可以选择性抑制 GP130 配体诱导的下游信号通路的激活，但 SC144 的溶解度较差且代谢不稳定。最近，一系列第二代 SC144 类似物已被鉴定出，它们具有口服活性、水溶性，并显示出理想的药代动力学。 (PK) 特性适合高级临床前研究。 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的结直肠癌 (CRC) 新鉴定的 SC144 的水溶性类似物。具有改善的 PK 特性，应在发展为结肠炎相关异常增生和癌症的结直肠炎症模型中测试其抗肿瘤活性，应评估 SC144 类似物的抗肿瘤活性。抑制肿瘤形成并调节相关生物标志物。 参考： 1. Jones S.A.、Scheller J.、Rose-John S. IL-6/gp130 信号传导的临床阻断的治疗策略。 J Clin Invest 121：3375-3383，2011。 2. Hong S.-S 等人，一种针对 IL-6 受体 β 亚基、糖蛋白 130 的新型小分子抑制剂。JImmunol 195：237-245，2015。 3. Xu S.，Neamati N. gp130：一种有前景的癌症治疗药物靶点。Expert Opin Ther Targets 17:1303-1328，2013。 4. Jones S.A.、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 18:773-789，2018。 5. Taher M.Y.、Davies D.M.、Maher J。白介素 (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. 指导从先天免疫到获得性免疫的转变：定义 IL-6 的作用，《免疫杂志》175：3463-3468，2005。 7. Johnson D.E.、O'Keefe R.A.、Grandis J.R. 针对癌症中的 IL-6/JAK/STAT3 信号轴。Nat Rev Clin Oncol 15：234-248，2018。 8. Grivennikov S.I., Karin M. 危险的联系：STAT3 和 NF-kappaB 的协作和癌症中的串扰。Rev 21:11-19，2010。 先前的研究发现 SC144 是一种首创、有效、安全且具有口服活性的 GP130 抑制剂 [3]，它可以选择性抑制 GP130 配体诱导的下游信号通路的激活，但 SC144 的溶解度较差且代谢不稳定。最近，一系列第二代 SC144 类似物已被鉴定出，它们具有口服活性、水溶性，并显示出理想的药代动力学。 (PK) 特性适合高级临床前研究。 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的结直肠癌 (CRC) 新鉴定的 SC144 的水溶性类似物。具有改善的 PK 特性，应在发展为结肠炎相关异常增生和癌症的结直肠炎症模型中测试其抗肿瘤活性，应评估 SC144 类似物的抗肿瘤活性。抑制肿瘤形成并调节相关生物标志物。