Small Molecule Inhibitors of the Inflammatory Cytokine Oncostatin M

炎症细胞因子制瘤素 M 的小分子抑制剂

• 批准号: 10438068
• 负责人: Don L Warner
• 金额: $ 39.54万
• 依托单位: BOISE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-18 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10438068
• 关键词: Affinity; Anti-Inflammatory Agents; Binding; Binding Sites; Biological Assay; Breast Cancer Patient; Breast Cancer cell line; Breast cancer metastasis; Cancer Etiology; Cell Survival; Cells; Cessation of life; Chromatography; Complex; Computer Models; Cystic Fibrosis; Data; Detection; Development; Diagnosis; Disease; Distant Metastasis; Docking; Drops; Education; Enzyme-Linked Immunosorbent Assay; Equipment; Event; FDA approved; Family; Fluorescence; Future; Goals; Human; In Vitro; Incentives; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interleukin-6; Intervention; Knowledge; Lead; Link; Localized Disease; Lupus; MDA MB 231; Malignant Neoplasms; Mammary Neoplasms; Measures; Mediating; Mentors; Metastatic breast cancer; Modeling; Monoclonal Antibodies; Neoplasm Metastasis; Nonmetastatic; Nuclear Magnetic Resonance; Patients; Pharmaceutical Preparations; Prognosis; Property; Proteins; Public Health; Quality of life; Recurrence; Reporting; Research; Rheumatoid Arthritis; Role; Science; Sepsis; Serum; Signal Pathway; Signal Transduction; Structure; Structure-Activity Relationship; Students; Survival Rate; System; Systemic Therapy; T47D; Testing; Therapeutic; Toxic effect; Training; Transitional Cell; Tumor Tissue; United States; United States National Institutes of Health; Western Blotting; Woman; analog; base; career; cytokine; design; detection method; drug development; epithelial to mesenchymal transition; experimental study; improved; in silico; in vitro testing; instrumentation; malignant breast neoplasm; metastasis prevention; migration; nanomolar; neoplastic cell; new therapeutic target; novel; novel therapeutics; oncostatin M; overexpression; patient prognosis; programs; receptor; receptor binding; scaffold; screening; small molecule; small molecule inhibitor; small molecule libraries; therapeutic target; undergraduate student; wound healing

PROJECT SUMMARY/ABSTRACT This project will synthesize and study small molecules inhibitors (SMIs) that bind to and inhibit signaling of the inflammatory cytokine, oncostatin M (OSM) as part of a long-term program to generate an FDA-approved drug for early protection against breast tumor metastasis and other OSM-associated diseases. In 2021, more than 281,000 new cases of invasive breast cancer are expected to be diagnosed in the United States. The five-year survival rate is 99% for patients diagnosed with localized disease but drops to 27% for those with distant metastases, underscoring a need for therapeutics that protect against the early stages of metastasis, when intervention could be most beneficial. Relevant to this proposal, OSM signaling promotes many metastatic- related events, including an epithelial to mesenchymal transition and tumor cell detachment, migration, and invasion. Importantly, OSM signaling is associated with a poor prognosis for breast cancer patients. Breast cancer patients with high levels of tumor tissue OSM correlated with a significant decrease in survival compared to those with low OSM levels. It was also determined that serum concentrations of OSM from both non-metastatic and metastatic breast cancer patients was significantly higher than levels in serum from healthy individuals (3.8-fold and 4.9-fold, respectively). For this proposal, preliminary experiments used a high throughput computational screen of ~1.65 million compounds for binding to OSM. Those compounds with the best predicted binding properties were tested for in vitro inhibition of OSM signaling. Two SMIs were identified as lead compounds for this proposal. The central hypothesis guiding the proposed experiments is that structural optimization based on lead SMIs, facilitated by knowledge of important binding interactions, will result in enhanced inhibition of OSM signaling. To test the hypothesis, two specific aims are proposed: 1) Design and synthesize a focused library of small molecule inhibitors of OSM based on the SMI-10 and SMI- 26 scaffolds and 2) Identify optimal lead SMIs that suppress OSM signaling in cells and display minimal cellular toxicity. In Aim 1, the NMR solution structure of an SMI/OSM complex will be solved and then combined with computational modeling to develop a structure-activity model that will be used to design and synthesize new SMIs. In Aim 2, SMIs will be prioritized based on high binding affinity, high in vitro inhibition of OSM-mediated signaling pathways in several breast cancer cell lines, and low cellular toxicity. The end goal of the project is to identify new compounds with nanomolar binding affinity to OSM and improved inhibitory activity. The proposed research will assist in fulfilling the critical need to develop novel treatments for metastatic breast cancer—often described as an “incurable” disease. Since OSM has been linked to other cancers and inflammatory-related diseases (e.g., sepsis, rheumatoid arthritis, and cystic fibrosis), this research lays the groundwork for a new class of anti-inflammatory drugs.

项目概要/摘要 该项目将合成并研究小分子抑制剂（SMI），这些抑制剂能够结合并抑制信号传导 炎症细胞因子制瘤素 M (OSM) 作为生产 FDA 批准药物的长期计划的一部分 用于早期预防乳腺肿瘤转移和其他 OSM 相关疾病。 2021 年，超过 美国预计将诊断出 281,000 例新的浸润性乳腺癌病例。五年来 诊断为局部疾病的患者的生存率为 99%，但诊断为远处转移的患者的生存率降至 27% 转移，强调需要针对转移的早期阶段提供保护的治疗方法，当 干预可能是最有益的。与该提议相关的是，OSM 信号传导促进许多转移- 相关事件，包括上皮细胞向间质细胞的转变以及肿瘤细胞的脱离、迁移和 入侵。重要的是，OSM 信号传导与乳腺癌患者的不良预后相关。 肿瘤组织 OSM 水平高的乳腺癌患者生存率显着下降 与那些 OSM 水平较低的人相比。还确定了两种物质中 OSM 的血清浓度 非转移性和转移性乳腺癌患者血清中的水平显着高于健康人 个人（分别是 3.8 倍和 4.9 倍）。对于这个建议，初步实验使用了高 约 165 万种与 OSM 结合的化合物的吞吐量计算筛选。那些化合物具有 测试了 OSM 信号传导的体外抑制的最佳预测结合特性。确定了两个 SMI 作为该提案的先导化合物。指导所提出的实验的中心假设是 基于先导 SMI 的结构优化，通过了解重要的结合相互作用来促进， 将导致 OSM 信号传导的增强抑制。为了检验该假设，提出了两个具体目标： 1）基于SMI-10和SMI-设计并合成OSM小分子抑制剂的重点库 26 个支架和 2) 识别抑制细胞中 OSM 信号传导并显示最小细胞的最佳先导 SMI 毒性。在目标 1 中，将解析 SMI/OSM 复合物的 NMR 溶液结构，然后将其与 计算建模来开发结构-活动模型，该模型将用于设计和合成新的 SMI。在目标 2 中，SMI 将基于高结合亲和力、对 OSM 介导的高体外抑制作用进行优先排序 多种乳腺癌细胞系中的信号通路，并且细胞毒性低。该项目的最终目标是 鉴定与 OSM 具有纳摩尔结合亲和力并改善抑制活性的新化合物。拟议的 研究将有助于满足开发转移性乳腺癌新疗法的迫切需求——通常 被称为“不治之症”。由于 OSM 与其他癌症和炎症相关 疾病（例如败血症、类风湿性关节炎和囊性纤维化），这项研究为新类别奠定了基础 抗炎药。