Bcl-xL is a validated therapeutic target whose systemic inhibition is limited by on-target toxicity. PROTAC-mediated degradation offers a strategy to widen this therapeutic margin by exploiting tissue-selective E3 ligase expression together with cooperative ternary complex formation. These complementary mechanisms restrict efficient Bcl-xL degradation to disease-relevant cells while enhancing degradation potency and selectivity, illustrating how targeted protein degradation can transform the therapeutic index of targets otherwise constrained by systemic pharmacological inhibition.

SARM1 illustrates an underappreciated liability of developing drugs that target active state in cooperative assemblies. At partial occupancy, active-site inhibitors can stabilize the active conformation and promote catalytically competent assemblies while leaving unoccupied sites functional, producing paradoxical activation. This mechanism highlights a general risk for multimeric or heteromeric complexes in which ligand binding, conformational switching, and protein–protein association are coupled.