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

Sökning: WFRF:(Altun M) > Inhibition of the u...

Elfman, LHM (författare)

Young, P (författare)

Lundback, T (författare)

Eirich, J (författare)

(creator_code:org_t)

2021-10-06
2021
Engelska.
Ingår i: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 12:10, s. 914-

Relaterad länk:: https://www.nature.c...; visa fler...; http://kipublication...; https://doi.org/10.1...; visa färre...

Abstract Ämnesord

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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.

Av författaren/redakt...: Giovannucci, TA; Salomons, FA; Haraldsson, M; Elfman, LHM; Wickstrom, M; Young, P; visa fler...; Lundback, T; Eirich, J; Altun, M; Jafari, R; Gustavsson, AL; Johnsen, JI; Dantuma, NP; visa färre...

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