Design of novel c-Met inhibitors inspired by olive phenolics

受橄榄酚类启发的新型 c-Met 抑制剂的设计

• 批准号: 8434417
• 负责人: KHALID A EL SAYED
• 金额: $ 42.05万
• 依托单位: UNIVERSITY OF LOUISIANA AT MONROE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8434417
• 关键词: Acids; Affinity; Alcohols; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Biological Assay; Breast Cancer Cell; Cancer cell line; Carbamates; Cardiovascular Diseases; Cells; Chronic; Clinical Research; Cognition Disorders; Computer Assisted; Coupling; Development; Diet; ERBB2 gene; Epidermal Growth Factor Receptor; Esters; Future; Goals; Growth; Hepatocyte Growth Factor; Human; In Vitro; Incidence; Individual; Inhibitory Concentration 50; Knowledge; Ligands; Lignans; Liquid substance; MCF7 cell; Malignant Neoplasms; Measures; Mediterranean Diet; Methodology; Methods; Neoplasm Metastasis; Olive oil preparation; Olives - dietary; Oncogenic; Outcome; PC3 cell line; PECAM1 gene; Parents; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Play; Prevention; Protein Tyrosine Kinase; Proto-Oncogene Protein c-met; Proto-Oncogenes; Publications; Receptor Protein-Tyrosine Kinases; Research; Role; SKBR3; Signal Pathway; Source; Techniques; Technology; Testing; Therapeutic; Therapeutic Effect; Therapeutic Index; Time; Tyrosine Kinase Inhibitor; Work; age related; amberlite; amberlite XAD 7; analog; angiogenesis; base; c new; cancer prevention; cancer therapy; cell growth; cost effective; density; design; dietary supplements; improved; in vivo; inhibitor/antagonist; lapatinib; malignant breast neoplasm; meetings; migration; novel; preclinical study; public health relevance; receptor; screening; small molecule; therapeutic development; tumor; tyrosol

DESCRIPTION (provided by applicant): Dysregulated activation c-Met receptor tyrosine kinase and its ligand HGF enhance cell growth, invasion, angiogenesis, metastasis, reduction of apoptosis, and change cytoskeletal functions of many tumors. Therefore, targeting c-Met activity with small molecule inhibitors of HGF/c-Met can be used for cancer treatment and prevention. The Mediterranean diet correlates with lower incidences of cardiovascular disease, age-related cognitive disease and cancer. A computer-assisted study identified (-)-oleocanthal (1), a natural secoiridoid from extra-virgin olive oil (EVOO), as a potential c-Met inhibitor hit. Oleocanthal inhibited in-vitro the phosphorylation of c-Met kinase, proliferation, migration, and invasion of te human breast and prostate cancer cell lines MCF7, MDA-MB-231 and PC-3, respectively. It also showed anti-angiogenic activity via downregulating the expression of CD31 in endothelial colony forming cells. Our long-term goal is to utilize the ability of olive oil secoiridoids like oleocantal to inhibit the activation of c-Met and use them as dietary supplements to synergize the therapeutic effects of chemotherapeutics like the dual EGFR and HER2 tyrosine kinase inhibitor (TKI) lapatinib. The present objective is to develop a new EVOO secoiridoids rich fraction (EVOOSRF) via simple extraction methodology and test the mixture and individual components' ability to inhibit the c-Met tyrosine kinase. Our central hypothesis is that dietary-based EVOOSRF and secoiridoid-related analogs can synergize the therapeutic effects of the currently used receptor TKIs when concomitantly used for c-Met dependent malignancies. The rationale for the proposed research is that gaining new knowledge concerning the mechanism and c-Met inhibitory activity of EVOO secoiridoid ingredients will facilitate the development of therapeutic approaches for remedy of c-Met-dependent malignancies. We will test our central hypothesis, and thereby accomplish the objective of this application by pursuing the following specific aims: 1: Optimization of standardized EVOO secoiridoid rich fraction. 2: Rationale design and synthesis of c-Met inhibitory tyrosol-based analogs. 3: Assessment of c-Met inhibitory, in vitro, and in vivo activities of EVOOSRF and new tyrosol analogs alone and in combination with receptor tyrosine kinase inhibitors. The expected outcomes of the work proposed in specific aims 1-3 will include the development of novel c-Met inhibitor dietary supplement (EVOOSRF) or synthetic analogs appropriate for further future preclinical and clinical studies. Anticipated new information will facilitate important therapeutic advances for alleviation and prevention of c-Met dependent malignancies.

描述（由申请人提供）：失调的c-Met受体酪氨酸激酶激活及其配体HGF增强细胞生长、侵袭、血管生成、转移、减少细胞凋亡，并改变许多肿瘤的细胞骨架功能。因此，利用 HGF/c-Met 小分子抑制剂靶向 c-Met 活性可用于癌症的治疗和预防。地中海饮食与心血管疾病、与年龄相关的认知疾病和癌症的发病率较低有关。一项计算机辅助研究发现 (-)-oleocanthal (1) 是一种来自特级初榨橄榄油 (EVOO) 的天然环烯醚萜苷，是一种潜在的 c-Met 抑制剂。油橄榄素在体外分别抑制人乳腺癌和前列腺癌细胞系 MCF7、MDA-MB-231 和 PC-3 的 c-Met 激酶磷酸化、增殖、迁移和侵袭。它还通过下调内皮集落形成细胞中 CD31 的表达而显示出抗血管生成活性。我们的长期目标是利用橄榄油环烯醚萜类化合物（如油酸康塔尔）抑制 c-Met 活化的能力，并将其用作膳食补充剂，以协同 EGFR 和 HER2 酪氨酸激酶双重抑制剂 (TKI) 拉帕替尼等化疗药物的治疗效果。目前的目标是通过简单的提取方法开发一种新的富含 EVOO 环烯醚萜成分 (EVOOSRF)，并测试混合物和单个成分抑制 c-Met 酪氨酸激酶的能力。我们的中心假设是，当同时用于 c-Met 依赖性恶性肿瘤时，基于饮食的 EVOOSRF 和环烯醚萜相关类似物可以协同目前使用的受体 TKI 的治疗效果。拟议研究的基本原理是，获得有关 EVOO 环烯醚萜成分的机制和 c-Met 抑制活性的新知识将有助于开发治疗 c-Met 依赖性恶性肿瘤的治疗方法。我们将测试我们的中心假设，从而通过追求以下具体目标来实现本申请的目标： 1：标准化的富含EVOO环烯醚萜级分的优化。图 2：c-Met 抑制性酪醇类似物的设计原理和合成。图3：评估EVOOSRF和新酪醇类似物单独以及与受体酪氨酸激酶抑制剂组合的c-Met抑制、体外和体内活性。具体目标 1-3 中提出的工作的预期成果将包括开发新型 c-Met 抑制剂膳食补充剂 (EVOOSRF) 或适合未来进一步临床前和临床研究的合成类似物。预期的新信息将促进缓解和预防 c-Met 依赖性恶性肿瘤的重要治疗进展。