Cellular model system to dissect the isoform-selectivity of Akt inhibitors

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dc.contributor.authorQuambusch, Lena
dc.contributor.authorDepta, Laura
dc.contributor.authorLandel, Ina
dc.contributor.authorLubeck, Melissa
dc.contributor.authorKirschner, Tonia
dc.contributor.authorNabert, Jonas
dc.contributor.authorUhlenbrock, Niklas
dc.contributor.authorWeisner, Jörn
dc.contributor.authorKostka, Michael
dc.contributor.authorLevy, Laura M.
dc.contributor.authorSchultz-Fademrecht, Carsten
dc.contributor.authorGlanemann, Franziska
dc.contributor.authorAlthoff, Kristina
dc.contributor.authorMüller, Matthias P.
dc.contributor.authorSiveke, Jens T.
dc.contributor.authorRauh, Daniel
dc.date.accessioned2021-12-09T12:46:16Z
dc.date.available2021-12-09T12:46:16Z
dc.date.issued2021-09-06
dc.description.abstractThe protein kinase Akt plays a pivotal role in cellular processes. However, its isoforms’ distinct functions have not been resolved to date, mainly due to the lack of suitable biochemical and cellular tools. Against this background, we present the development of an isoform-dependent Ba/F3 model system to translate biochemical results on isoform specificity to the cellular level. Our cellular model system complemented by protein X-ray crystallography and structure-based ligand design results in covalent-allosteric Akt inhibitors with unique selectivity profiles. In a first proof-of-concept, the developed molecules allow studies on isoform-selective effects of Akt inhibition in cancer cells. Thus, this study will pave the way to resolve isoform-selective roles in health and disease and foster the development of next-generation therapeutics with superior on-target properties.en
dc.identifier.urihttp://hdl.handle.net/2003/40596
dc.identifier.urihttp://dx.doi.org/10.17877/DE290R-22465
dc.language.isoende
dc.relation.ispartofseriesNature Communications;12
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectCell cultureen
dc.subjectChemical toolsen
dc.subjectKinasesen
dc.subjectStructure-based drug designen
dc.subjectX-ray crystallographyen
dc.subject.ddc570
dc.subject.ddc540
dc.titleCellular model system to dissect the isoform-selectivity of Akt inhibitorsen
dc.typeTextde
dc.type.publicationtypearticlede
dcterms.accessRightsopen access
eldorado.secondarypublicationtruede
eldorado.secondarypublication.primarycitationQuambusch, L., Depta, L., Landel, I. et al. Cellular model system to dissect the isoform-selectivity of Akt inhibitors. Nat Commun 12, 5297 (2021). https://doi.org/10.1038/s41467-021-25512-8de
eldorado.secondarypublication.primaryidentifierhttps://doi.org/10.1038/s41467-021-25512-8de

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