Novel c-Met inhibitory olive secoiridoid semisynthetic analogs for the control of invasive breast cancer

Abstract

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.

The olive oil phenolic (-)-oleocanthal modulates estrogen receptor expression in luminal breast cancer in vitro and in vivo and synergizes with tamoxifen treatment

“…Earlier studies indicated that (−)-oleocanthal is a potential inhibitor of the hepatocyte growth factor receptor (c-Met) pathway in breast cancer cells (Akl et al, 2014; Elnagar et al, 2011; Mohyeldin et al, 2016b). The antiproliferative effects of (−)-oleocanthal are mediated by inhibiting multiple c-Met downstream signaling molecules including protein kinase B (Akt), mitogen-activated protein kinase (MAPK), signal transducers and activators of transcription-3 (STAT-3), and mammalian target of rapamycin (mTOR) in multiple cancer cells (Akl et al, 2014; Fogli et al, 2016; Khanal et al, 2011; Khanfar et al, 2015; Pei et al, 2016; Scotece et al, 2013).…”

The Maxi-K (BK) Channel Antagonist Penitrem A as a Novel Breast Cancer-Targeted Therapeutic

“…In silico binding studies were performed using Schrödinger molecular modeling software (v9, Schrodinger, New York, NY, USA), as previously described [ 56 ]. The calcium site domain of each of the BK channel crystal structure PDB codes 3NAF and 3MT5, resolution ≥3 Å, was prepared using the protein preparation wizard, applying PROPKA (Jensen Research Group, Denmark) to add hydrogens, assign bond orders, and optimize hydrogen bonding networks.…”

“…The LigPrep wizard using OPLS force field was chosen to prepare the 3D-dimensional structure of each analog, undergo geometric optimization, search for different conformers, and calculate partial atomic charges. Docking of penitrems was then conducted using the Glide 5.8 module (Glide, 2012, Schrodinger, New York, NY, USA) in extra-precision (XP) mode or in standard-precision mode (SP) [ 56 ].…”

Identification of Phytochemicals Targeting c-Met Kinase Domain using Consensus Docking and Molecular Dynamics Simulation Studies

“…In the case of ZINC03871891 bound to the active conformation, it did not form hydrogen bond with any residues in the hinge region, a typical characteristic of all kinase inhibitors targeting the ATP-binding site [25,35]. Instead, hydrophobic interactions were found with M1160, suggesting a lower binding affinity with an IC 50 of 18.76 nM.…”