Project description
Targeted protein degradation in cancer therapy
A major goal of modern medicine is the development of tools that can selectively target cancer cells. Acute myeloid leukemia (AML) is an aggressive blood cancer of the myeloid cells causing bone marrow failure. The high concentrations of drugs inhibiting the activity of proteins promoting cell proliferation often lead to off-target effects. Recently, the technique that employs proteolysis targeting chimeras (PROTACs) showed promising therapeutic effects by the degradation of disease-causing proteins. The EU-funded RECOBIN-PROTACs project proposes a novel rational design and synthesis of reversible covalently binding PROTACs based on proximity labelling. A RECOBIN-PROTAC molecule consists of a target protein ligand, an E3 ligase ligand and a chemoselective functional group connected through flexible linkers selectively releasing the active RECOBIN-PROTAC inside the target cells upon protease cleavage.
Objective
Today's challenge for modern medicine is the development of tools that can selectively target cancer cells over healthy cells. Acute myeloid leukemia (AML) is an aggressive blood cancer of the myeloid cells causing bone marrow failure. Drug development research uses small molecules to inhibit the activity of proteins promoting cell proliferation. The higher concentrations of drug required for efficient inhibition often lead to off-target effects. Recent years, proteolysis targeting chimeras (PROTACs) technique receives much attention for therapeutic intervention by degradation of disease-causing proteins. However, the requirements of PROTACs such as high affinity and specificity ligands, poor stability, cell permeability, lack of cell specificity limit the broader utility of this technique. Here, we propose a novel rational design and synthesis of reversible covalently binding PROTACs (RECOBIN-PROTACs) based on the proximity labeling. A RECOBIN-PROTAC molecule consists of target protein ligand, E3 ligase ligand and a chemoselective functional group connected through flexible linkers. The chemoselective functional group forms reversible covalent modification with proximal Lys residue of BET protein or E3 ligase. This proximity labeling enhances the binding affinity of the ligands to the targets, stabilizing protein-protein interactions in ternary complex formation. The library of RT53 based RECOBIN-PROTACs will be tested on AML cell lines to find most efficient degraders. Also, the chemoselective group masked by self-immolative linker connects with enzyme-labile group and cysteine reactive handle. The most efficient RT53 based RECOBIN-PROTACs will be conjugated site-selectively to cysteine antibody to generate stable RECOBIN-PROTAC-Antibody Conjugates. These conjugates selectively release the active RECOBIN-PROTAC inside the target cells upon protease cleavage. The features of RECOBIN-PROTACs technology will bring new modalities in therapies and drug discovery.
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.
- medical and health sciences basic medicine pharmacology and pharmacy drug discovery
- natural sciences biological sciences biochemistry biomolecules proteins proteomics
- medical and health sciences clinical medicine oncology leukemia
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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-EF-ST - Standard EF
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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-2019
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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.
CB2 1TN CAMBRIDGE
United Kingdom
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.