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

• DOI: 10.1111/cas.15733
• Publication Date: 2023-01-24T12:49:26Z
• Authors: Jin‐Jiao Chen; Jin‐Mei Jin; Wen‐Jie Gu; Zeng Zhao; Hu Yuan; Yu‐Dong Zhou; Dale G. Nagle; Qiu‐Lei Xi; Xue‐Mei Zhang; Qing‐Yan Sun; Ye Wu; Wei‐Dong Zhang; Xin Luan
• Keywords: Protein Degradation; Proteolysis; Cullin; Cereblon

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