{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Zhang P"],"funding":["NCI NIH HHS","National Institutes of Health"],"pagination":["3495-3506"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12155403"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["16(8)"],"pubmed_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 (IC<sub>50</sub> = 1.3 nM) and ∼6-fold enhanced degradation potency against Bcl-xL (DC<sub>50</sub> = 0.9 nM) as well as superior potency across multiple SCLC cell lines compared to XZ739"],"journal":["RSC medicinal chemistry"],"pubmed_title":["Discovery of PZ671, a highly potent and &lt;i&gt;in vivo&lt;/i&gt; active CRBN-recruiting Bcl-xL degrader."],"pmcid":["PMC12155403"],"funding_grant_id":["R01CA241191","R01CA260239","R01 CA241191","R01 CA260239"],"pubmed_authors":["Thummuri D","He Y","Hu W","Zhang X","Zhou D","Lv D","Zheng G","Pal P","Zhang P","Khan S"],"additional_accession":[]},"is_claimable":false,"name":"Discovery of PZ671, a highly potent and &lt;i&gt;in vivo&lt;/i&gt; active CRBN-recruiting Bcl-xL degrader.","description":"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 (IC<sub>50</sub> = 1.3 nM) and ∼6-fold enhanced degradation potency against Bcl-xL (DC<sub>50</sub> = 0.9 nM) as well as superior potency across multiple SCLC cell lines compared to XZ739","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Aug","modification":"2026-06-03T05:54:15.826Z","creation":"2026-04-25T03:16:49.736Z"},"accession":"S-EPMC12155403","cross_references":{"pubmed":["40510905"],"doi":["10.1039/d5md00119f"]}}