Targeted cancer therapies are a new class of anticancer drugs that inhibit therapeutic targets which are specifically up-regulated or activated in tumors thus minimizing the damage to normal cells. While cancer patients initially respond to targeted therapy, rapidly acquired resistance to kinase inhibitors remains one of the biggest challenges in the treatment of cancer patients. Increased production of hepatocyte growth factor (HGF), the activating ligand for MET receptor tyrosine kinase, is a common mechanism of resistance to these drugs. Accordingly, levels of HGF are elevated in the tumor microenvironment and in the serum of cancer patients that fail to respond to targeted therapy. Currently, there is no FDA-approved drugs that would target the ligand HGF or receptor MET selectively. ProteXase Therapeutics is developing the first small molecule inhibitors of HGF activation called synthetic HGF Activator Inhibitors (sHAIs). These compounds are specifically designed to inhibit the serine proteases, HGF-Activator (HGFA), matriptase and hepsin. These proteases are the major HGF processing enzymes which convert secreted, inactive proHGF to active HGF. One or more of these enzymes are necessary for proteolytically activating HGF in the tumor microenvironment. Without this activation HGF is not able to activate MET kinase signaling. We have shown that sHAIs have potent anticancer activity in multiple cancer types including breast, prostate, pancreas, lung, colon cancer. We have also demonstrated sHAIs can both overcome and prevent resistance to EGFR and MET-targeted therapeutic agents (small molecule kinase inhibitors and receptor antibodies) in colon and lung cancer. ProteXase is focused on the rational drug discovery and development of sHAIs as a more effective treatment option for lung and colon cancer patients, including those which are resistant to current therapies.