Synthesis and identification of a novel selective USP7 degrader that inhibits the migration of upper gastrointestinal cancer cells without affecting proliferation.

USP7 has been reported to promote cancer progression through removing ubiquitin from various substrates, making it a target for cancer therapy. To now, several USP7 proteolysis-targeting chimeras (PROTACs) have been reported, and USP7 inhibitors used in USP7 PROTACs all feature tert-hydroxypiperidinol scaffold. In this study, we firstly designed and synthesized a panel of novel USP7 PROTACs with USP7 inhibitor containing thienopyridine, and identified D16 as a potent and selective USP7 degrader. Mechanistic investigation with specific inhibitors revealed that D16 induced USP7 degradation by binding to USP7 and E3 ligase CRBN. Proteomics analysis showed that D16 selectively decreased the expression of USP7 rather than other USPs. Moreover, treatment of D16 suppressed cell migration of upper gastrointestinal (UGI) cancer cells with minor anti-proliferative activity. Our findings highlight that D16 may support as a promising lead compound for metastatic UGI cancer treatment.