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

Elucidating specific effects of protein kinase Akt isoforms remains challenging. Here, the authors establish an Akt isoform-dependent cellular model system and use it, together with X-ray crystallography and structure-based ligand design, to develop isoform-selective covalent-allosteric Akt inhibitors 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.

Automated summary

The study focuses on elucidating the specific effects of protein kinase Akt isoforms by establishing an Akt isoform-dependent cellular model system and developing isoform-selective covalent-allosteric Akt inhibitors through X-ray crystallography and structure-based ligand design. This approach allows for the study of isoform-selective effects of Akt inhibition in cancer cells, potentially paving the way for the development of next-generation therapeutics with superior on-target properties.