WFRF:(Altun M)
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| Fältnamn | Indikatorer | Metadata |
|---|---|---|
| 000 | 03295naa a2200433 4500 | |
| 001 | oai:prod.swepub.kib.ki.se:147786460 | |
| 003 | SwePub | |
| 008 | 240916s2021 | |||||||||||000 ||eng| | |
| 024 | 7 | a http://kipublications.ki.se/Default.aspx?queryparsed=id:1477864602 URI |
| 024 | 7 | a https://doi.org/10.1038/s41419-021-04191-92 DOI |
| 040 | a (SwePub)ki | |
| 041 | a engb eng | |
| 042 | 9 SwePub | |
| 072 | 7 | a ref2 swepub-contenttype |
| 072 | 7 | a art2 swepub-publicationtype |
| 100 | 1 | a Giovannucci, TAu Karolinska Institutet4 aut |
| 245 | 1 0 | a Inhibition of the ubiquitin-proteasome system by an NQO1-activatable compound |
| 264 | c 2021-10-06 | |
| 264 | 1 | b Springer Science and Business Media LLC,c 2021 |
| 520 | a 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. | |
| 650 | 7 | a MEDICIN OCH HÄLSOVETENSKAPx Medicinsk bioteknologix Medicinsk bioteknologi0 (SwePub)304012 hsv//swe |
| 650 | 7 | a MEDICAL AND HEALTH SCIENCESx Medical Biotechnologyx Medical Biotechnology0 (SwePub)304012 hsv//eng |
| 700 | 1 | a Salomons, FAu Karolinska Institutet4 aut |
| 700 | 1 | a Haraldsson, Mu Karolinska Institutet4 aut |
| 700 | 1 | a Elfman, LHM4 aut |
| 700 | 1 | a Wickstrom, Mu Karolinska Institutet4 aut |
| 700 | 1 | a Young, P4 aut |
| 700 | 1 | a Lundback, T4 aut |
| 700 | 1 | a Eirich, J4 aut |
| 700 | 1 | a Altun, Mu Karolinska Institutet4 aut |
| 700 | 1 | a Jafari, Ru Karolinska Institutet4 aut |
| 700 | 1 | a Gustavsson, ALu Karolinska Institutet4 aut |
| 700 | 1 | a Johnsen, JIu Karolinska Institutet4 aut |
| 700 | 1 | a Dantuma, NPu Karolinska Institutet4 aut |
| 710 | 2 | a Karolinska Institutet4 org |
| 773 | 0 | t Cell death & diseased : Springer Science and Business Media LLCg 12:10, s. 914-q 12:10<914-x 2041-4889 |
| 856 | 4 | u https://www.nature.com/articles/s41419-021-04191-9.pdf |
| 856 | 4 8 | u http://kipublications.ki.se/Default.aspx?queryparsed=id:147786460 |
| 856 | 4 8 | u https://doi.org/10.1038/s41419-021-04191-9 |
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- Altun, M
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