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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-depende...
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Published in: | European journal of medicinal chemistry 2016-08, Vol.118, p.299-315 |
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Main Authors: | , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | 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.
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•Inspired by (−)-oleocanthal, HVS-16 was discovered as a novel c-Met inhibitor hit.•HVS-16 impaired Met-mediated cellular events across 2D & 3D breast cancer cultures.•HVS-16 had no effect on both non-cancerous and Met-independent breast cancer cells.•Inhibition of c-Met activation was confirmed by Western blot and docking studies. |
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ISSN: | 0223-5234 1768-3254 1768-3254 |
DOI: | 10.1016/j.ejmech.2016.04.043 |