Project description
New targeted protein therapies for hard-to-treat diseases
The ability to break down previously ‘undruggable’ proteins has opened new doors in therapeutic development. Targeted protein degradation leverages the ubiquitin-proteasome system to eliminate disease-causing proteins rather than merely inhibiting them. While degraders, including molecular glue degraders and proteolysis-targeting chimeras, have shown clinical success, they rely on a narrow set of E3 ligases (helper proteins that tag others for destruction) that limits tissue specificity and causes drug resistance. Supported by the Marie Skłodowska-Curie Actions programme, the SdCoDEL-TPD project seeks to create new degraders that work well with E3 ligases. Researchers will use advanced techniques to identify specific sites on E3 ligases where these degraders can bind. Project results could improve drug design and open new possibilities for tackling certain cancer types.
Objective
Targeted protein degradation (TPD) via the ubiquitin-proteasome system (UPS) has emerged as a powerful therapeutic strategy with the potential to tackle “undruggable” proteins by surpassing occupancy-driven inhibition. Degraders are mainly classified into molecular glue degraders (MGDs) and proteolysis-targeting chimeras (PROTACs). Despite the clinical success of MGDs such as thalidomide and the progress of over 50 degrader candidates into clinical trials, current approaches rely heavily on a small subset of E3 ligases, particularly VHL and CRBN. This leads to resistance and limits tissue specificity, underscoring the need to expand the E3 ligase repertoire and develop novel degraders. A key barrier is that PROTACable sites, where E3 ligases induce TPD, remain largely undefined, and scalable strategies for discovering new E3 ligase ligands are lacking. This proposal addresses these challenges by developing degraders from novel covalent E3 ligase ligands discovered through site-specific ligand incorporation-induced proximity (SLIP) combined with covalent DNA-encoded library (CoDEL) selection. The core of this approach is the use of activity-based protein profiling (ABPP) of hydroxy O-nucleophilic residues to guide SLIP validation, revealing new PROTACable sites on E3 ligases, followed by CoDEL selection to discover covalent ligands that engage these sites. The platform, SdCoDEL-TPD, will apply newly identified covalent ligands in PROTAC design and evaluate their efficacy for targets challenging to degrade through CRBN- or VHL- based PROTACs, such as EML4-ALK and the Bcr-AblT315I mutant. The potential of these covalent ligands to function as MGDs will also be explored. By mapping PROTACable sites and enabling the discovery of covalent ligands across previously inaccessible E3 ligases, SdCoDEL-TPD will generate unprecedented E3 ligase resources, advance rational design of degraders, expand the scope of TPD applications, and potentially deliver new therapeutic insights.
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.
This project's classification has been human-validated.
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.
This project's classification has been human-validated.
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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HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA)
MAIN PROGRAMME
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Topic(s)
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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.
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships
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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) HORIZON-MSCA-2025-PF
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SW7 2AZ London
United Kingdom
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