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Bioactivatable inhibitor of ubiquitin-dependent proteasomal degradation

ABSTRACT: The hyperactive state of malignant cells results in the production of an excess of aberrant proteins that challenge the clearing capacity of the ubiquitin-proteasome system (UPS), resulting in an increased sensitivity towards drugs that reduce the efficacy of this critical proteolytic system. In this project we report the identification of an inhibitor that subsequent to cellular metabolism inhibits the UPS.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

SUBMITTER: Rozbeh Jafari

LAB HEAD: Janne Lehtiö

PROVIDER: PXD019519 | Pride | 2021-11-03

REPOSITORIES: Pride

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

Giovannucci Tatiana A TA Salomons Florian A FA Haraldsson Martin M Elfman Lotta H M LHM Wickström Malin M Young Patrick P Lundbäck Thomas T Eirich Jürgen J Altun Mikael M Jafari Rozbeh R Gustavsson Anna-Lena AL Johnsen John Inge JI Dantuma Nico P NP

Cell death & disease 20211006 10

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-indep ...[more]

PMID: 34615851

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