Discovery of Small Molecules PC Inhibitors

Discovery of Small Molecules PC Inhibitors

(Group : Preprotein Convertases, Tumor Invasion and Metastasis)

Taking advantage of the fact that the PCs are synthesized as inactive proenzymes we found that the pro-peptides or prosegments of the PCs possess a potent inhibitory effect against the cognate enzyme. Lately, we were able to chemically synthesize and produce the 83-mer full length pro-peptide of human furin (ppfurin) using solid phase peptide chemistry methodology. This synthetic peptide was found to inhibit furin activity in vitro in a competitive manner with inhibition constant Ki at low nM range. Treatment of cells with this peptide blocked furin-mediated cleavage of furin substrates in a dose dependent manner.

We also identified that the flavonoid baicalein, isolated from the medicinally active plant Oroxylum indicum (OI) acts also as an inhibitor of furin. These inhibitors were found to inhibit the malignant phenotype of tumor cells.

Similarly, the use of Virtual Ligand Screening (VLS) based on the catalytic site of the convertase furin (only convertase with published crystallographic structure) and ChemBridge database (over 500 000 unique molecules), several molecules were found to inhibit significantly the catalytic activity of furin and tumor cells proliferation and migration (Matrigel). We are now testing these compounds on the malignant phenotype of tumor cells using various in vivo models including the zebrafish model.

The 4 best inhibitors (blue) docked into the Furin active site (Green). These inhibitors are able to inhibit tumor cells (e. g. human colon carcinoma HT-29) proliferation and migration.