Design of novel c-Met inhibitors inspired by olive phenolics

描述（由申请人提供）：c-Met受体酪氨酸激酶及其配体HGF的激活异常促进许多肿瘤的细胞生长、侵袭、血管生成、转移、减少凋亡和改变细胞骨架功能。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。地中海饮食与较低的心血管疾病、与年龄相关的认知疾病和癌症发病率相关。一项计算机辅助研究发现(-)-油酸(1)，一种从特级初榨橄榄油（EVOO）中提取的天然环烯醚酮，是一种潜在的c-Met抑制剂。油柑素在体外分别抑制人乳腺癌和前列腺癌细胞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的环烯醚萜类化合物，如油辛醛，抑制c-Met的激活，并将其作为膳食补充剂，协同化疗药物的治疗效果，如双重EGFR和HER2酪氨酸激酶抑制剂（TKI）拉帕替尼。本研究的目的是通过简单的提取方法制备一种新的EVOOSRF，并测试其混合物和单个成分对c-Met酪氨酸激酶的抑制能力。我们的中心假设是，当同时用于c-Met依赖性恶性肿瘤时，以饮食为基础的EVOOSRF和环烯醚酮相关类似物可以协同目前使用的受体TKIs的治疗效果。提出这项研究的基本原理是，获得关于EVOO二环烯醚萜类成分的机制和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。我们将检验我们的中心假设，从而通过追求以下具体目标来实现本应用的目标：1：标准化EVOO seciiridoid富馏分的优化。2: c-Met抑制性酪氨酸类似物的基本原理设计和合成。3：评估EVOOSRF和新的酪氨酸类似物单独使用和与受体酪氨酸激酶抑制剂联合使用时c-Met的抑制作用、体外和体内活性。具体目标1-3中提出的工作预期结果将包括开发新型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。

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.