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

ABSTRACT: 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

SUBMITTER: Zhang P 

PROVIDER: S-EPMC12155403 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature