Macrocyclic Inhibitors of HGF-Activating Serine Proteases Overcome Resistance to Receptor Tyrosine Kinase Inhibitors and Block Lung Cancer Progression

Hepatocyte growth factor (HGF), the
ligand for the MET receptor
tyrosine kinase, is a tumor-promoting factor that is abundant in the
tumor microenvironment. Proteolytic activation of inactive pro-HGF
by one or more of the serine endopeptidases matriptase, hepsin, and
HGF activator is the rate-limiting step in HGF/MET signaling. Herein,
we have rationally designed a novel class of side chain cyclized macrocyclic
peptide inhibitors. The new series of cyclic tripeptides has superior
metabolic stability and significantly improved pharmacokinetics in
mice relative to the corresponding linear peptides. We identified
the lead compound VD2173 that potently inhibits matriptase and hepsin,
which was tested in parallel alongside the acyclic inhibitor ZFH7116
using both in vitro and in vivo models of lung cancer. We demonstrated
that both compounds block pro-HGF activation, abrogate HGF-mediated
wound healing, and overcome resistance to EGFR- and MET-targeted therapy
in lung cancer models. Furthermore, VD2173 inhibited HGF-dependent
growth of lung cancer tumors in mice.