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

Xiuxiu Lu, Venkata R. Sabbasani, Vasty Osei-Amponsa, Christine N. Evans, Julianna C. King, Sergey G. Tarasov, Marzena Dyba, Sudipto Das, King C. Chan, Charles D. Schwieters, Sulbha Choudhari, Caroline Fromont, Yongmei Zhao, Bao Tran, Xiang Chen, Hiroshi Matsuo, Thorkell Andresson, Raj Chari, Rolf E. Swenson, Nadya I. Tarasova and Kylie J. Walters ()
Additional contact information
Xiuxiu Lu: National Institutes of Health
Venkata R. Sabbasani: National Institutes of Health
Vasty Osei-Amponsa: National Institutes of Health
Christine N. Evans: Frederick National Laboratory for Cancer Research
Julianna C. King: Frederick National Laboratory for Cancer Research
Sergey G. Tarasov: National Institutes of Health
Marzena Dyba: National Institutes of Health
Sudipto Das: Leidos Biomedical Research, Inc
King C. Chan: Leidos Biomedical Research, Inc
Charles D. Schwieters: National Institutes of Health
Sulbha Choudhari: Frederick National Laboratory for Cancer Research
Caroline Fromont: Frederick National Laboratory for Cancer Research
Yongmei Zhao: Frederick National Laboratory for Cancer Research
Bao Tran: Frederick National Laboratory for Cancer Research
Xiang Chen: National Institutes of Health
Hiroshi Matsuo: Frederick National Laboratory for Cancer Research
Thorkell Andresson: Leidos Biomedical Research, Inc
Raj Chari: Frederick National Laboratory for Cancer Research
Rolf E. Swenson: National Institutes of Health
Nadya I. Tarasova: National Institutes of Health
Kylie J. Walters: National Institutes of Health

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-27570-4

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