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.

项目总结/摘要 该项目将合成和研究小分子抑制剂（SMI），结合并抑制信号传导的 炎症细胞因子，制瘤素M（OSM）作为一个长期计划的一部分，以产生FDA批准的药物 早期预防乳腺癌转移和其他OSM相关疾病。2021年，超过 预计美国将诊断出281，000例新的浸润性乳腺癌病例。五年 诊断为局限性疾病的患者的存活率为99%，但对于那些远处转移的患者，存活率下降到27%。 转移，强调了对保护免于早期转移阶段的治疗剂的需要，当 干预可能是最有益的。与该提议相关，OSM信号传导促进许多转移性- 相关事件，包括上皮向间质转化和肿瘤细胞脱离、迁移， 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著降低 与低OSM水平的人相比。还确定了两者的OSM血清浓度 非转移性和转移性乳腺癌患者血清中的水平显著高于健康人血清中的水平。 个体（分别为3.8倍和4.9倍）。对于这个提议，初步实验使用了一个高 通过计算筛选约165万种化合物与OSM结合。这些化合物与 测试了最佳预测的结合特性对OSM信号传导的体外抑制。确定了两个SMI 作为这个提议的先导化合物。指导拟议实验的中心假设是， 基于主要SMI的结构优化，通过重要结合相互作用的知识来促进， 将导致OSM信号传导的增强抑制。为了检验这一假设，提出了两个具体目标： 1)基于SMI-10和SMI-10设计并合成OSM的小分子抑制剂的聚焦库。 2）鉴定抑制细胞中OSM信号传导并显示最小细胞毒性的最佳先导SMI。 毒性在目标1中，将求解SMI/OSM络合物的NMR溶液结构，然后与 计算建模，以开发结构活性模型，该模型将用于设计和合成新的 SMIs。在目标2中，SMI将基于高结合亲和力、高体外抑制OSM介导的细胞毒性、高生物相容性和高生物相容性而被优先考虑。 在几种乳腺癌细胞系中的信号传导途径，和低细胞毒性。该项目的最终目标是 鉴定对OSM具有纳摩尔结合亲和力和改善的抑制活性的新化合物。拟议 研究将有助于满足开发转移性乳腺癌新疗法的迫切需要， 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），这项研究为一个新的类别奠定了基础。 消炎药的副作用