Novel c Met inhibitory olive secoiridoid semisynthetic analogs for the control of invasive breast cancer.
Dysregulated receptor tyrosine kinase c Met and its ligand HGF is valid and attractive molecular target for therapeutic blockade in cancer. Inspired by the chemical structure of the naturally occurring olive secoiridoid oleocanthal (1) and its documented anticancer activity against c Met dependent malignancies, a previous study reported tyrosol sinapate (4) as a c Met inhibitor hit. This study reports additional semisynthetic optimization and SAR of 4 to improve its selective activity against c Met dependent breast cancer by increasing its capacity to inhibit c Met phosphorylation. Forty three compounds (5 47) were synthesized, among which the novel analog homovanillyl sinapate (HVS 16) was distinguished for its remarkable activity. HVS 16 substantially impaired c Met mediated proliferation, migration, and invasion across human breast cancer cell lines in two and three dimensional culture systems, while similar treatment doses were found to have effect neither on the non tumorigenic human mammary epithelial cell growth nor on the c Met independent breast cancer cell viability. HVS 16 showed a dose dependent inhibition of ligand mediated c Met activation in human breast cancer cells. Docking studies revealed that HVS 16 fits very well inside c Met crystal structures, satisfying critical interactions at the ATP binding site. This study identified important structural pharmacophoric features in HVS 16 and correlated its postulated binding pose with c Met kinase assay data that would guide future olive secoiridoid bioisostere lead design. Results presented herein suggest HVS 16 as a promising c Met inhibitor validated hit with potential to control invasive breast malignancies with aberrant c Met activity.
European journal of medicinal chemistry