{"entity": "researcher", "timestamp": "2026-09-24T14:45:56.586Z", "family": "Giovannucci", "given": "Tatiana A", "initials": "TA", "orcid": "0000-0001-8978-6318", "affiliations": ["Department of Cell and Molecular Biology (CMB), Karolinska Institutet, Stockholm, Sweden."], "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/researcher/e15d22f9b0dd4895be76ad3d1125b4a9.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/researcher/e15d22f9b0dd4895be76ad3d1125b4a9"}}, "publications": [{"entity": "publication", "iuid": "3a10a87b8a7345c28b3b7c38b69c7d73", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/3a10a87b8a7345c28b3b7c38b69c7d73.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/3a10a87b8a7345c28b3b7c38b69c7d73"}}, "title": "Identification of a novel compound that simultaneously impairs the ubiquitin-proteasome system and autophagy.", "authors": [{"family": "Giovannucci", "given": "Tatiana A", "initials": "TA", "orcid": "0000-0001-8978-6318", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/e15d22f9b0dd4895be76ad3d1125b4a9.json"}}, {"family": "Salomons", "given": "Florian A", "initials": "FA"}, {"family": "Stoy", "given": "Henriette", "initials": "H"}, {"family": "Herzog", "given": "Laura K", "initials": "LK"}, {"family": "Xu", "given": "Shanshan", "initials": "S"}, {"family": "Qian", "given": "Weixing", "initials": "W"}, {"family": "Merino", "given": "Lara G", "initials": "LG"}, {"family": "Gierisch", "given": "Maria E", "initials": "ME"}, {"family": "Haraldsson", "given": "Martin", "initials": "M"}, {"family": "Lystad", "given": "Alf H", "initials": "AH"}, {"family": "Uvell", "given": "Hanna", "initials": "H"}, {"family": "Simonsen", "given": "Anne", "initials": "A", "orcid": "0000-0003-4711-7057", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/044853ac09a642c88a1b461eaf915ecd.json"}}, {"family": "Gustavsson", "given": "Anna-Lena", "initials": "AL"}, {"family": "Vallin", "given": "Michaela", "initials": "M"}, {"family": "Dantuma", "given": "Nico P", "initials": "NP", "orcid": "0000-0002-6090-4170", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/0828f330ff9b47d689c3770b05951dbe.json"}}], "type": "journal article", "published": "2022-07-00", "journal": {"title": "Autophagy", "issn": "1554-8635", "volume": "18", "issue": "7", "pages": "1486-1502", "issn-l": "1554-8627"}, "abstract": "The ubiquitin-proteasome system (UPS) and macroautophagy/autophagy are the main proteolytic systems in eukaryotic cells for preserving protein homeostasis, i.e., proteostasis. By facilitating the timely destruction of aberrant proteins, these complementary pathways keep the intracellular environment free of inherently toxic protein aggregates. Chemical interference with the UPS or autophagy has emerged as a viable strategy for therapeutically targeting malignant cells which, owing to their hyperactive state, heavily rely on the sanitizing activity of these proteolytic systems. Here, we report on the discovery of CBK79, a novel compound that impairs both protein degradation by the UPS and autophagy. While CBK79 was identified in a high-content screen for drug-like molecules that inhibit the UPS, subsequent analysis revealed that this compound also compromises autophagic degradation of long-lived proteins. We show that CBK79 induces non-canonical lipidation of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 beta) that requires ATG16L1 but is independent of the ULK1 (unc-51 like autophagy activating kinase 1) and class III phosphatidylinositol 3-kinase (PtdIns3K) complexes. Thermal preconditioning of cells prevented CBK79-induced UPS impairment but failed to restore autophagy, indicating that activation of stress responses does not allow cells to bypass the inhibitory effect of CBK79 on autophagy. The identification of a small molecule that simultaneously impairs the two main proteolytic systems for protein quality control provides a starting point for the development of a novel class of proteostasis-targeting drugs.", "doi": "10.1080/15548627.2021.1988359", "pmid": "34740308", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC9298443"}], "notes": [], "created": "2026-09-23T13:13:25.831Z", "modified": "2026-09-23T13:13:25.927Z"}, {"entity": "publication", "iuid": "8e7b370673ec474280252b303c77e103", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/8e7b370673ec474280252b303c77e103.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/8e7b370673ec474280252b303c77e103"}}, "title": "Inhibition of the ubiquitin-proteasome system by an NQO1-activatable compound.", "authors": [{"family": "Giovannucci", "given": "Tatiana A", "initials": "TA", "orcid": "0000-0001-8978-6318", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/e15d22f9b0dd4895be76ad3d1125b4a9.json"}}, {"family": "Salomons", "given": "Florian A", "initials": "FA"}, {"family": "Haraldsson", "given": "Martin", "initials": "M"}, {"family": "Elfman", "given": "Lotta H M", "initials": "LHM"}, {"family": "Wickstr\u00f6m", "given": "Malin", "initials": "M", "orcid": "0000-0001-5214-9956", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/338ea31865c44e0d86a9947dbed04a28.json"}}, {"family": "Young", "given": "Patrick", "initials": "P"}, {"family": "Lundb\u00e4ck", "given": "Thomas", "initials": "T", "orcid": "0000-0002-8145-7808", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/09fcf2bbaaad4f86a98ad55fa626bda4.json"}}, {"family": "Eirich", "given": "J\u00fcrgen", "initials": "J", "orcid": "0000-0003-0963-1872", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/3070defe1f614b57ab391fa9a15c39a2.json"}}, {"family": "Altun", "given": "Mikael", "initials": "M", "orcid": "0000-0002-6937-6124", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/d77b74fe6e7d44f4800fe8bb4404ad8f.json"}}, {"family": "Jafari", "given": "Rozbeh", "initials": "R", "orcid": "0000-0002-3396-4709", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/95546f158dde40709fbfbb822a8f89c5.json"}}, {"family": "Gustavsson", "given": "Anna-Lena", "initials": "AL"}, {"family": "Johnsen", "given": "John Inge", "initials": "JI", "orcid": "0000-0003-1277-812X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/e63aa6bb0fba481abeb58c2f1568b3c9.json"}}, {"family": "Dantuma", "given": "Nico P", "initials": "NP", "orcid": "0000-0002-6090-4170", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/0828f330ff9b47d689c3770b05951dbe.json"}}], "type": "journal article", "published": "2021-10-06", "journal": {"title": "Cell Death Dis", "issn": "2041-4889", "volume": "12", "issue": "10", "pages": "914", "issn-l": "2041-4889"}, "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.", "doi": "10.1038/s41419-021-04191-9", "pmid": "34615851", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC8494907"}, {"db": "pii", "key": "10.1038/s41419-021-04191-9"}], "notes": [], "created": "2026-09-23T13:00:08.530Z", "modified": "2026-09-23T13:00:08.701Z"}]}