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Closing the gap: studying non-obvious ligand induced degradation events

Project description

Advancing the therapeutic potential of protein inhibitor drugs

Kinase enzymes have been intensively investigated as drug targets for years. However, little is known about the destabilisation impact of inhibitor drugs following binding to the target enzyme. The EU-funded MapInDegraders project aims to map such destabilising events using an in vitro assay that monitors kinase stability. Combined with multidisciplinary analyses, the project will shed light on the protein, chemical and biophysical properties that influence the downstream effect of drug binding. Collectively, results will shed light on an underexplored space with large translational potential for future medical applications.

Objective

Inhibitor-induced target destabilisation has been reported sporadically in recent years. Importantly, despite never actually having been put in place on purpose – or by design – these effects often play a significant role towards their therapeutic effect. To date, no systematic approach to map or quantify these serendipitous destabilising events has, however, been performed, representing a huge underexplored space with large translational potential. I here propose to study ligand-induced destabilisation by utilising the plethora of available protein kinase inhibitors to systematically map their kinase degrading abilities. First, an innovative in vivo assay will be developed to monitor kinase stability at scale. Next a protein kinase inhibitor library will be screened and inhibitor-destabilised kinase pairs will be identified using automated high-throughput microscopy, coupled to fluorescent activated cell sorting and next generation sequencing. Pharmacokinetic mode-of-action binning and machine-learning based computational data mining will chart the map of ligand-induced destabilisation and delineate crucial protein, chemical and/or biophysical properties. Finally, based on the principal mode-of-action identification, measured effect size and translational potential, in-depth mechanism of action studies will be conducted for one selected inhibitor-kinase pair. To that end, a multi-omics approach consisting of genome-wide CRISPR screens and orthogonal genomics and proteomics strategies will be conducted. The project will delineate the underlying concepts of ligand-induced destabilisation using protein kinase inhibitors as a chemically well explored compound space and thus open new avenues to tap into the translationally intriguing area of designing targeted protein degraders for future medical applications.

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Coordinator

CEMM - FORSCHUNGSZENTRUM FUER MOLEKULARE MEDIZIN GMBH
Net EU contribution
€ 174 167,04
Address
Lazarettgasse 14 akh bt 25.3
1090 Wien
Austria

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Region
Ostösterreich Wien Wien
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Links
Other funding
€ 0,00