biostudies-literatureZhang PNCI NIH HHSNational Institutes of Health3495-3506https://www.ebi.ac.uk/biostudies/studies/S-EPMC12155403biostudies-literatureUnknown16(8)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 XZ739RSC medicinal chemistryDiscovery of PZ671, a highly potent and <i>in vivo</i> active CRBN-recruiting Bcl-xL degrader.PMC12155403R01CA241191R01CA260239R01 CA241191R01 CA260239Thummuri DHe YHu WZhang XZhou DLv DZheng GPal PZhang PKhan SfalseDiscovery of PZ671, a highly potent and <i>in vivo</i> 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 XZ7392025-01-01T00:00:00Z2025 Aug2026-06-03T05:54:15.826Z2026-04-25T03:16:49.736ZS-EPMC121554034051090510.1039/d5md00119f