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 Müller, Jens T. Siveke, Daniel Rauh
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.