Authors: Quambusch, Lena
Depta, Laura
Landel, Ina
Lubeck, Melissa
Kirschner, Tonia
Nabert, Jonas
Uhlenbrock, Niklas
Weisner, Jörn
Kostka, Michael
Levy, Laura M.
Schultz-Fademrecht, Carsten
Glanemann, Franziska
Althoff, Kristina
Müller, Matthias P.
Siveke, Jens T.
Rauh, Daniel
Title: Cellular model system to dissect the isoform-selectivity of Akt inhibitors
Language (ISO): en
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.
Subject Headings: Cell culture
Chemical tools
Structure-based drug design
X-ray crystallography
Issue Date: 2021-09-06
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Appears in Collections:Medizinische Chemie und Chemische Biologie

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