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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 (hRpn13 Pru ) present naturally with cell type-dependent abundance.  XL5 -PROTACs preferentially target hRpn13 Pru , 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 hRpn13 Pru -producing cancer types.

Structure-guided bifunctional molecules hit a DEUBAD-lacking hRpn13 species upregulated in multiple myeloma