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.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences genetics
- natural sciences biological sciences biochemistry biomolecules proteins proteomics
- natural sciences computer and information sciences data science data mining
- natural sciences physical sciences optics microscopy
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions
MAIN PROGRAMME
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H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility
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Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)
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Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) H2020-MSCA-IF-2020
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Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.
1090 Wien
Austria
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.