Crizotinib-based proteolysis targeting chimera suppresses gastric cancer by promoting MET degradation

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Gastric cancer (GC) presents a significant challenge due to late diagnosis and poor prognosis.
• Overexpression of receptor tyrosine kinase MET correlates with advanced GC and poor patient outcomes.
• Existing MET inhibitors face limitations, including acquired resistance, necessitating novel therapeutic approaches.

Purpose of the Study:

• To develop a novel therapeutic strategy for MET-dependent gastric cancer by targeting MET protein degradation.
• To design and synthesize proteolysis targeting chimeras (PROTACs) capable of degrading MET proteins.
• To evaluate the efficacy of a lead PROTAC compound in preclinical models of gastric cancer.

Main Methods:

• Transformed the MET-targeted inhibitor crizotinib into a series of PROTACs.
• Utilized cereblon/cullin 4A E3 ubiquitin ligase for MET protein degradation.
• Assessed PROTAC efficacy in vitro (cell lines) and in vivo (MKN-45 xenograft model).

Main Results:

• The optimized lead PROTAC, PRO-6E, effectively degraded MET proteins in vitro and in vivo.
• PRO-6E demonstrated inhibition of proliferation and motility in MET-positive GC cells.
• PRO-6E exhibited significant antitumor efficacy in a xenograft model with good tolerability.

Conclusions:

• PRO-6E represents the first oral PROTAC developed for MET-dependent gastric cancer.
• This PROTAC strategy shows promise for overcoming resistance associated with conventional MET inhibitors.
• PRO-6E offers a potential new therapeutic avenue for treating advanced gastric cancer.