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

Lena Quambusch, Laura Depta, Ina Landel, Melissa Lubeck, Tonia Kirschner, Jonas Nabert, Niklas Uhlenbrock, Jörn Weisner, Michael Kostka, Laura M. Levy, Carsten Schultz-Fademrecht, Franziska Glanemann, Kristina Althoff, Matthias P. Müller, Jens T. Siveke and Daniel Rauh ()
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Lena Quambusch: TU Dortmund University and Drug Discovery Hub Dortmund (DDHD), Zentrum für Integrierte Wirkstoffforschung (ZIW)
Laura Depta: TU Dortmund University and Drug Discovery Hub Dortmund (DDHD), Zentrum für Integrierte Wirkstoffforschung (ZIW)
Ina Landel: TU Dortmund University and Drug Discovery Hub Dortmund (DDHD), Zentrum für Integrierte Wirkstoffforschung (ZIW)
Melissa Lubeck: TU Dortmund University and Drug Discovery Hub Dortmund (DDHD), Zentrum für Integrierte Wirkstoffforschung (ZIW)
Tonia Kirschner: TU Dortmund University and Drug Discovery Hub Dortmund (DDHD), Zentrum für Integrierte Wirkstoffforschung (ZIW)
Jonas Nabert: TU Dortmund University and Drug Discovery Hub Dortmund (DDHD), Zentrum für Integrierte Wirkstoffforschung (ZIW)
Niklas Uhlenbrock: TU Dortmund University and Drug Discovery Hub Dortmund (DDHD), Zentrum für Integrierte Wirkstoffforschung (ZIW)
Jörn Weisner: TU Dortmund University and Drug Discovery Hub Dortmund (DDHD), Zentrum für Integrierte Wirkstoffforschung (ZIW)
Michael Kostka: Taros Chemicals GmbH & Co. KG
Laura M. Levy: Taros Chemicals GmbH & Co. KG
Carsten Schultz-Fademrecht: Lead Discovery Center GmbH
Franziska Glanemann: University Medicine Essen
Kristina Althoff: University Medicine Essen
Matthias P. Müller: TU Dortmund University and Drug Discovery Hub Dortmund (DDHD), Zentrum für Integrierte Wirkstoffforschung (ZIW)
Jens T. Siveke: University Medicine Essen
Daniel Rauh: TU Dortmund University and Drug Discovery Hub Dortmund (DDHD), Zentrum für Integrierte Wirkstoffforschung (ZIW)

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract The 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.

Date: 2021
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DOI: 10.1038/s41467-021-25512-8

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