VHL and cancer: Nonetheless,two VHL-based PROTACs, the Bcl-xL degrader DT2216 and Astellas’sKRASG12D degrader ASP-3082, have also entered clinicaltrials.13,14 Resistance against CRBN and VHL-based PROTACsdevelops through mutations and/or downregulation of the ubiquitinligase machinery,69−72 raising concerns about the effectiveness of current PROTACs againsthighly mutation-prone cancer cells and motivating a need for identifyingand developing alternative E3 ligase ligands.