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• W3123529451 abstract "Napabucasin, undergoing multiple clinical trials, was reported to inhibit the signal transducer and transcription factor 3 (STAT3). To better elucidate its mechanism of action, we designed a napabucasin-based proteolysis targeting chimera (PROTAC), XD2-149 that resulted in inhibition of STAT3 signaling in pancreatic cancer cell lines without inducing proteasome-dependent degradation of STAT3. Proteomics analysis of XD2-149 revealed the downregulation of the E3 ubiquitin-protein ligase ZFP91. XD2-149 degrades ZFP91 with DC50 values in the nanomolar range. The cytotoxicity of XD2-149 was significantly, but not fully, reduced with ZFP91 knockdown providing evidence for its multi-targeted mechanism of action. The NQO1 inhibitor, dicoumarol, rescued the cytotoxicity of XD2-149 but not ZFP91 degradation, suggesting that the NQO1-induced cell death is independent of ZFP91. ZFP91 plays a role in tumorigenesis and is involved in multiple oncogenic pathways including NF-κB and HIF-1α." @default.
• W3123529451 created "2021-02-01" @default.
• W3123529451 creator A5007802460 @default.
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• W3123529451 date "2021-01-28" @default.
• W3123529451 modified "2023-10-15" @default.
• W3123529451 title "Discovery of a Napabucasin PROTAC as an Effective Degrader of the E3 Ligase ZFP91" @default.
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• W3123529451 doi "https://doi.org/10.1021/acs.jmedchem.0c01897" @default.
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