 The study presents the use of the E3 ligase receptor DCAF1 for targeted protein degradation, TPD, using a selective, non-covalent binder, and demonstrates its effectiveness in chemical and genetic rescue experiments. Additionally, the study shows that Dacetina-based DCAF1-PITACs can successfully degrade cytosolic and membrane-bound tyrosine kinases, and provides an alternative strategy to tackling intrinsic resistance to VHL degrader using a potent and selective DCAF1, BTK, Protac, DBT-10. Overall, the study highlights the potential of DCAF1-PITACs as a promising strategy to overcome ligase-mediated resistance in clinical settings.