Stefan 2022 Abstract Bioblast

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8.4. «7+3»
Stefan Eduard
Stefan Eduard (2022) Tracking patient-mutation and lead-molecule driven alterations of kinase activity conformations. Bioblast 2022: BEC Inaugural Conference. In: https://doi.org/10.26124/bec:2022-0001

Link: Bioblast 2022: BEC Inaugural Conference

Stefan Eduard (2022)

Event: Bioblast 2022

Kinases function as molecular switches for coordinating spatiotemporal signal transmission. Genomic alterations affect kinase abundance and/or their activities which contribute to the etiology and progression of diseases such as distinct cancers and Parkinson’s disease (PD). Thus, major drug discovery efforts aim to identify lead molecules targeting the clinically relevant kinase entity. The concept of personalized medicine aims to apply the therapeutic agent with the highest efficacy towards a patient-specific target protein mutation. We have recently implemented a cell-based reporter system which fosters the decision-making process for identifying and selecting efficient lead molecules. We have engineered a modular kinase conformation (KinCon) biosensor platform for live-cell analyses of kinase activity states. This biosensor facilitates the recording of kinase activity conformations of the wild-type and the respective mutated kinase upon lead-molecule or approved-drug exposure. First, in proof-of-principle studies we have demonstrated that this technology is suitable for the systematic determination of melanoma drug efficacies using the full-length KinCon reporters for BRAF and MEK which harbor distinct cancer patient mutations (Röck et al., Science Advances 2019, Mayrhofer et al., PNAS 2020, Fleischmann et al., Biomolecules 2021). Second, we have extended KinCon reporters to quantify the activity-relevant formation of multimeric kinase complexes, involving members of the RIPK [inflammation] or CDK [cancer] kinase families. Third, recently we have engineered mitochondria associated biosensors to analyze and categorize PD kinase mutations. Thus, with new KinCon reporters we are setting out to characterize PD causing kinase gain-of-function mutations and to reactivate a PD kinase displaying a collection of loss-of-function mutations, directly in an intact cell setting. Finally, we would like to underline that this precision-medicine-oriented KinCon biosensor concept is not restricted to recordings of kinase drug efficacies/specificities. We have first evidence that such conformation reporter can extended to other (pseudo)enzyme categories.

Keywords: Molecular switch, Kinase biosensor, Undruggable, Off-target effects, Drug efficacies

O2k-Network Lab: AT Innsbruck Oroboros


Affiliations

Institute of Biochemistry and Center for Molecular Biosciences, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria
Tyrolean Cancer Research Institute & KinCon biolabs, Innrain 66, 6020 Innsbruck, Austria

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Event: B4