Profiling of diverse tumor types establishes the broad utility of VHL-based ProTaCs and triages candidate ubiquitin ligases.
Bioengineering
Cancer
Molecular biology
Journal
iScience
ISSN: 2589-0042
Titre abrégé: iScience
Pays: United States
ID NLM: 101724038
Informations de publication
Date de publication:
18 Mar 2022
18 Mar 2022
Historique:
received:
09
12
2019
revised:
01
11
2021
accepted:
24
02
2022
entrez:
17
3
2022
pubmed:
18
3
2022
medline:
18
3
2022
Statut:
epublish
Résumé
The success of small molecule therapeutics that promotes degradation of critical cancer targets has fueled an intense effort to mimic this activity with bispecific molecules called PROTACs (proteolysis targeting chimeras). The simultaneous binding of PROTACs to a ligase and target can induce proximity-driven ubiquitination and degradation. VHL and CRBN are the two best characterized PROTAC ligases, but the rules governing their cellular activities remain unclear. To establish these requirements and extend them to new ligases, we screened a panel of 56 cell lines with two potent PROTACs that utilized VHL, MZ1, or CRBN, dBET1 to induce degradation of BRD4. With notable exceptions, MZ1 was broadly active in the panel whereas dBET1 was frequently inactive. A search for predictive biomarkers of PROTAC activity found that expression and mutation of VHL and CRBN were themselves predictors of PROTAC activity in the cell line panel.
Identifiants
pubmed: 35295813
doi: 10.1016/j.isci.2022.103985
pii: S2589-0042(22)00255-3
pmc: PMC8919295
doi:
Types de publication
Journal Article
Langues
eng
Pagination
103985Informations de copyright
© 2022 The Author(s).
Déclaration de conflit d'intérêts
X.L., I.A., K.D., K.S., O.H., J.R.L., and D.M. were employees and stock holders of Amgen at the time of this report.
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