Synthetic Indolactam V Analogues as Inhibitors of PAR2‐Induced Calcium Mobilization in Triple‐Negative Breast Cancer Cells

Abstract

Human proteinase-activated receptor 2 (PAR2), a transmembrane G-protein-coupled receptor (GPCR), is an attractive target for a novel anticancer therapy, as it plays a critical role in cell migration and invasion. Selective PAR2 inhibitors therefore have potential as anti-metastatic drugs. Knowing that the natural product teleocidin A2 is able to inhibit PAR2 in tumor cells, the goal of the present study was to elaborate structure-activity relationships and to identify potent PAR2 inhibitors with lower activity against the adverse target, protein kinase C (PKC). For this purpose, an efficient gram-scale total synthesis of indolactam V (i.e., the parent structure of all teleocidins) was developed, and a library of derivatives was prepared. Some compounds were indeed found to exhibit high potency as PAR2 inhibitors at low nanomolar concentrations with improved selectivity (relative to teleocidin A2). The pseudopeptidic fragment bridging the C3 and C4 positions of the indole core proved to be essential for target binding, whereas activity and target selectivity depends on the substituents at N1 or C7. This study revealed novel derivatives that show high efficacy in PAR2 antagonism combined with increased selectivity.

GPCR Modulation in Breast Cancer

“…ENMD-1068 decreases in MCF-7 breast cancer cells the concentrations of granulocyte colony-stimulating factor (GCSF), a highly expressed cytokine correlated with poor survival [113,114]. Recently, structure–activity relationship studies have allowed the identification of promising selective PAR2 inhibitors including derivatives of teleocidin with high efficacy in inhibiting breast tumor cell migration [115]. Whether PAR2 antagonists could be considered as PAR1 antagonists and vice versa is a matter of interest given that PAR2 interacts with PAR1 to form a functional unit implied in breast tumor development [116].…”

Stationed or Relocating: The Seesawing EMT/MET Determinants from Embryonic Development to Cancer Metastasis

“…Sunitinib, a kinase inhibitor, was found to inhibit downstream CDC42 and RHO kinases 1 (ROCK1) functions by targeting G Protein-Coupled Receptor Kinase 5 (GRK5) to modulate the motility of triple-negative breast cancer cells [ 161 ]. Jan Stein et al found that teleocidin A2 can inhibit proteinase-activated receptor 2 (PAR2) in breast cancer [ 162 ]. Similarly, a coenzyme Q10 analog, decylubiquinone, was found to inhibit brain angiogenesis inhibitor 1 in breast cancer, thus inhibiting metastasis [ 163 ].…”