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Giovannucci TA, Salomons FA, Haraldsson M, et al. Inhibition of the ubiquitin-proteasome system by an NQO1-activatable compound. Cell Death Dis. 2021;12(10):914doi: 10.1038/s41419-021-04191-9.
Giovannucci, T. A., Salomons, F. A., Haraldsson, M., Elfman, L. H. M., Wickström, M., Young, P., Lundbäck, T., Eirich, J., Altun, M., Jafari, R., Gustavsson, A. L., Johnsen, J. I., & Dantuma, N. P. (2021). Inhibition of the ubiquitin-proteasome system by an NQO1-activatable compound. Cell death & disease, 12(10), 914. https://doi.org/10.1038/s41419-021-04191-9
Giovannucci, Tatiana A, et al. "Inhibition of the ubiquitin-proteasome system by an NQO1-activatable compound." Cell death & disease vol. 12,10 (2021): 914. doi: https://doi.org/10.1038/s41419-021-04191-9
Giovannucci TA, Salomons FA, Haraldsson M, Elfman LHM, Wickström M, Young P, Lundbäck T, Eirich J, Altun M, Jafari R, Gustavsson AL, Johnsen JI, Dantuma NP. Inhibition of the ubiquitin-proteasome system by an NQO1-activatable compound. Cell Death Dis. 2021 Oct 06;12(10):914. doi: 10.1038/s41419-021-04191-9. PMID: 34615851; PMCID: PMC8494907.
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Cell Death Dis. 2021 Oct 06;12(10):914. doi: 10.1038/s41419-021-04191-9.

Inhibition of the ubiquitin-proteasome system by an NQO1-activatable compound.

Cell death & disease

Tatiana A Giovannucci, Florian A Salomons, Martin Haraldsson, Lotta H M Elfman, Malin Wickström, Patrick Young, Thomas Lundbäck, Jürgen Eirich, Mikael Altun, Rozbeh Jafari, Anna-Lena Gustavsson, John Inge Johnsen, Nico P Dantuma

Affiliations

  1. Department of Cell and Molecular Biology (CMB), Karolinska Institutet, Stockholm, Sweden.
  2. Chemical Biology Consortium Sweden (CBCS), Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Stockholm, Sweden.
  3. Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
  4. Mechanistic & Structural Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden.
  5. Science for Life Laboratory, Department of Oncology-Pathology, Clinical Proteomics Mass Spectrometry, Karolinska Institutet, Solna, Stockholm, Sweden.
  6. Science for Life Laboratory, Department of Medical Biochemistry and Biophysics (MBB), Karolinska Institutet, Solna, Stockholm, Sweden.
  7. Institute of Plant Biology and Biotechnology, University of Muenster, 48143, Muenster, Germany.
  8. Science for Life Laboratory, Department of Laboratory Medicine, Karolinska Institutet, Solna, Stockholm, Sweden.
  9. Department of Cell and Molecular Biology (CMB), Karolinska Institutet, Stockholm, Sweden. [email protected].

PMID: 34615851 PMCID: PMC8494907 DOI: 10.1038/s41419-021-04191-9

Abstract

Malignant cells display an increased sensitivity towards drugs that reduce the function of the ubiquitin-proteasome system (UPS), which is the primary proteolytic system for destruction of aberrant proteins. Here, we report on the discovery of the bioactivatable compound CBK77, which causes an irreversible collapse of the UPS, accompanied by a general accumulation of ubiquitylated proteins and caspase-dependent cell death. CBK77 caused accumulation of ubiquitin-dependent, but not ubiquitin-independent, reporter substrates of the UPS, suggesting a selective effect on ubiquitin-dependent proteolysis. In a genome-wide CRISPR interference screen, we identified the redox enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1) as a critical mediator of CBK77 activity, and further demonstrated its role as the compound bioactivator. Through affinity-based proteomics, we found that CBK77 covalently interacts with ubiquitin. In vitro experiments showed that CBK77-treated ubiquitin conjugates were less susceptible to disassembly by deubiquitylating enzymes. In vivo efficacy of CBK77 was validated by reduced growth of NQO1-proficient human adenocarcinoma cells in nude mice treated with CBK77. This first-in-class NQO1-activatable UPS inhibitor suggests that it may be possible to exploit the intracellular environment in malignant cells for leveraging the impact of compounds that impair the UPS.

© 2021. The Author(s).

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