R13I

In this study, for the first time, we report the development of BTK-targeting degraders using the PROTAC strategy.These PROTACs could ef fi ciently degrade ibrutinib-sensitive BTK-WT (wild type).More importantly, our newly designed PROTACs also significantly induced the degradation of ibrutinib resistant BTK-C481S (50% degradation efficiency at 30 nM).Furthermore, our PROTAC mols. ef fi ciently inhibited cell proliferation and colony formation, while exhibited no obvious inhibition (>1000 nM) of ITK, EGFR, and TEC, which are major off-targets of ibrutinib.These data demonstrate the strong potential for developing PROTAC-based therapeutic mols.The results indicate that the PROTAC strategy (protein degradation instead of inhibition) could be adopted as a general and powerful therapeutic treatment for drug-resistant cancers in the future.