Matches in SemOpenAlex for { <https://semopenalex.org/work/W4225513441> ?p ?o ?g. }
- W4225513441 abstract "Proteasome substrate receptor hRpn13 is a promising anti-cancer target. By integrated in silico and biophysical screening, we identified a chemical scaffold that binds hRpn13 with non-covalent interactions that mimic the proteasome and a weak electrophile for Michael addition. hRpn13 Pru domain binds proteasomes and ubiquitin whereas its DEUBAD domain binds deubiquitinating enzyme UCHL5. NMR revealed lead compound XL5 to interdigitate into a hydrophobic pocket created by lateral movement of a Pru β-hairpin with an exposed end for Proteolysis Targeting Chimeras (PROTACs). Implementing XL5-PROTACs as chemical probes identified a DEUBAD-lacking hRpn13 species (hRpn13Pru) present naturally with cell type-dependent abundance. XL5-PROTACs preferentially target hRpn13Pru, causing its ubiquitination. Gene-editing and rescue experiments established hRpn13 requirement for XL5-PROTAC-triggered apoptosis. These data establish hRpn13 as an anti-cancer target for multiple myeloma and introduce an hRpn13-targeting scaffold that can be optimized for preclinical trials against hRpn13Pru-producing cancer types." @default.
- W4225513441 created "2022-05-05" @default.
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- W4225513441 date "2021-12-16" @default.
- W4225513441 modified "2023-10-06" @default.
- W4225513441 title "Structure-guided bifunctional molecules hit a DEUBAD-lacking hRpn13 species upregulated in multiple myeloma" @default.
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- W4225513441 doi "https://doi.org/10.1038/s41467-021-27570-4" @default.
- W4225513441 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/34916494" @default.
- W4225513441 hasPublicationYear "2021" @default.
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