Crizotinib-based PROTAC suppresses gastric cancer via promoting MET degradation.

As one of the common malignant cancer types, gastric cancer (GC) is known for late-stage diagnosis and poor prognosis. Over-expression of the receptor tyrosine kinase MET is associated with poor prognosis among patients with advanced stage of GC. However, no MET inhibitor has been used for GC treatment now. Like other tyrosine kinase inhibitors that fit the "occupancy-driven" model, current MET inhibitors are prone to acquired resistance. The emerging proteolysis targeting chimeric (PROTAC) strategy could overcome such limitations through direct degradation of the target proteins. In this study, we successfully transformed the MET-targeted inhibitor crizotinib into a series of PROTACs, recruiting Cereblon (CRBN)/cullin 4A E3 ubiquitin ligase to degrade the MET proteins. The optimized lead PROTAC (PRO-6E) effectively eliminated MET proteins in vitro and in vivo, inhibiting proliferation and motility of MET-positive GC cells. In the MKN-45 xenograft model, PRO-6E exhibited pronounced anti-tumor efficacy with a well-tolerated dosage regimen. These results validated PRO-6E as the first oral PROTAC for MET-dependent GC.