Design of novel c-Met inhibitors inspired by olive phenolics -
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.
