Abstract Dysregulation of the proto-oncogene receptor tyrosine kinase c-Met, which encodes the high-affinity receptor for hepatocyte growth factor (HGF) and the Hedgehog (Hh) pathway aberrantly associated with numerous malignancies including basal cell carcinoma, medulloblastoma, prostate, pancreatic and breast cancers. The Mediterranean diet is associated with lower incidences of cardiovascular disease, age-related cognitive disease and cancer. (-)-Oleocanthal is a naturally occurring minor secoiridoid from extra-virgin olive oil with potent anti-inflammatory activity via its ability to inhibit COX-1 and COX-2 and anti-Alzheimer's activity. Cyclopamine and its 11-oxo derivative jervine are C-nor-D-homosteroidal alkaloids with known potent teratogenic effects that induce cyclopic malformations in sheep. The jervane Veratrum alkaloids cyclopamine and jervine and the veratrane alkaloid veratramine were among the early known natural products that blocked the expression of the Hh pathway targets PTCH1 and GLI1, lowering Bcl2 levels and inducing apoptosis in many tumors. Computer-assisted molecular design (CAMD) identified oleocanthal as a potential virtual c-Met inhibitor hit. Oleocanthal inhibited the proliferation, migration, and invasion of the epithelial human breast and prostate cancer cell lines MCF7, MDA-MB-231, and PC-3, respectively. Oleocanthal demonstrated anti-angiogenic activity and inhibited the phosphorylation of c-Met kinase in vitro. CAMD study of our library of natural, biocatalytic, and semisynthetic jervane and veratrane alkaloids suggested that compounds with C-3-keto functionality with α4,5 or β1,2 and γ4,5 exhibited high virtual Hh binding affinity scores and possible Hh pathway activity. These compounds showed significant ability to inhibit the growth, proliferation, and migration of the prostate metastatic cancer cell line PC-3, which aided the establishment of a preliminary structure-activity relationship. (-)-Oleocanthal and Veratrum alkaloids can have potential therapeutic application for the control of c-Met- and Hh-dependent malignancies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4778. doi:1538-7445.AM2012-4778