Discovery of PZ671, a highly potent and in vivo active CRBN-recruiting Bcl-xL degrader.

The conversion of conventional inhibitors of Bcl-xL, a key anti-apoptotic protein, to PROTAC degraders has shown significant promise, particularly in mitigating the on-target thrombocytopenia associated with Bcl-xL inhibition but improving their potency. Previously, we reported XZ739, a CRBN-recruiting Bcl-xL PROTAC that was 20-fold more potent than its parent inhibitor ABT-263 against Bcl-xL-dependent MOLT-4 cells while reducing toxicity to human platelets. Building on XZ739, we here report the discovery of PZ671, a more potent Bcl-xL degrader with ∼10-fold improved cellular activity against MOLT-4 cells (IC50 = 1.3 nM) and ∼6-fold enhanced degradation potency against Bcl-xL (DC50 = 0.9 nM) as well as superior potency across multiple SCLC cell lines compared to XZ739. In vivo studies revealed that PZ671 could effectively inhibit MOLT-4 xenograft growth in mice but caused only a moderate and transient reduction in platelet counts following its administration. Our findings highlight the potential of CRBN-recruiting Bcl-xL degraders as promising anticancer agents with improved efficacy and manageable platelet toxicity.