Proteolysis-targeting chimeras (PROTACs) are molecules that induce proximity between
target proteins and E3 ligases triggering target protein degradation. Pomalidomide, a widely
used E3 ligase recruiter in PROTACs, can independently degrade other proteins, including
zinc-finger (ZF) proteins, with vital roles in health and disease. This off-target degradation
hampers the therapeutic applicability of pomalidomide-based PROTACs, requiring
development of PROTAC design rules that minimize off-target degradation. Here we …

ABSTRACT Proteolysis Targeting Chimeras (PROTACs), a class of heterobifunctional
molecules that recruit target proteins to E3 ligases, have gained traction for targeted protein
degradation. However, pomalidomide, a widely used E3 ligase recruiter in PROTACs, can
independently degrade other targets, such as zinc-finger (ZF) proteins, that hold key
functions in normal development and disease progression. This off-target degradation of
pomalidomidebased PROTACs raises concerns about their therapeutic applicability and …