Project description
Ubiquitin-independent targeted protein degradation strategies
Targeted protein degradation (TPD) is an emerging therapeutic strategy that leverages the ubiquitin-proteasome system to selectively degrade disease-causing proteins. One advanced method uses proteolysis-targeting chimeras (PROTACs) that bind an E3 ligase (E3) and a target protein to trigger ubiquitination and subsequent target destruction. While promising, the method’s dependence on E3s presents significant challenges. To address this, the ERC-funded NextTPD project will build on previous research, where it found that the fusion of short peptide motifs to target proteins can induce their ubiquitin-independent proteasomal degradation (UbInPD), eliminating the need for E3-based systems. It now aims to design novel PROTACs that incorporate UbInPD short peptide motifs to improve the TPD of model disease-associated proteins for cancer treatment.
Objective
The ubiquitin-proteasome system (UPS) is crucial for maintaining diverse cellular functions through the selective degradation of proteins. Targeted Protein Degradation (TPD) has emerged as an innovative therapeutic strategy that harnesses the UPS to selectively degrade disease-causing proteins. A major advancement in TPD is the use of proteolysis-targeting chimeras (PROTACs), small molecules that bind both an E3 ligase (E3) and the target protein, to induce ubiquitination and subsequent degradation of the target. While PROTACs have shown promise, their reliance on E3s poses challenges, including tissue-specific expression of E3s, the requirement for accessible ubiquitination sites on target proteins, and potential resistance mechanisms due to E3 mutations. Furthermore, only a small subset of E3s has been successfully utilized for TPD.
To address these challenges, this ERC PoC project explores an alternative approach: direct targeting of proteins to the proteasome for degradation, bypassing the need for ubiquitination. This strategy eliminates reliance on specific E3s and provides a broader, universal approach for proteolysis. During our ERC StG project, using cutting-edge proteomics technology, we identified short peptide motifs that when fused to target proteins, can promote their ubiquitin-independent proteasomal degradation (UbInPD). These findings present a novel opportunity to design PROTACs that directly recruit targets to the proteasome, bypassing the traditional limitations of E3-based systems.
Here, we aim to develop PROTACs incorporating UbInPD short peptide motifs to enhance TPD of model disease-associated proteins, such as the androgen receptor and BRD proteins, for cancer treatment. This approach could significantly broaden the scope of targetable proteins, opening up new avenues for drug discovery. Successful outcomes could lead to groundbreaking therapeutic applications and establish novel, ubiquitin-independent TPD strategies in precision medicine.
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 biochemistry biomolecules proteins proteomics
- natural sciences biological sciences genetics mutation
- medical and health sciences clinical medicine oncology
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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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HORIZON.1.1 - European Research Council (ERC)
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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.
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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-ERC-POC - HORIZON ERC Proof of Concept Grants
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Call for proposal
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(opens in new window) ERC-2025-POC
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52900 Ramat Gan
Israel
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