ExploDProteins
Financiado
Exploiting the DNA damage response to induce degradation of proteins
Here I propose to use small molecules to degrade proteins specifically around sites of DNA damage by using the damage itself as a homing signal. The approach will create new ways to study DNA damage, but will also offer translatio...
Here I propose to use small molecules to degrade proteins specifically around sites of DNA damage by using the damage itself as a homing signal. The approach will create new ways to study DNA damage, but will also offer translational possibilities in cancer. Cancer cells are often acutely sensitive to DNA damage because they have one or more faulty DNA damage response (DDR) pathways – a feature that makes them highly dependent on their remaining DNA repair systems. We will pioneer two novel and related chemical approaches for selectively killing cancer cells by modulating DDR pathways with bifunctional DNA damaging molecules. We will do this by reprogramming E3 ligases. E3 ligases are modular multi-protein complexes that destabilize cellular proteins by catalysing the formation of polyubiquitin chains on its substrates, which serve as a signal for proteasomal degradation. A recent revolutionary advance in chemical biology is to use small molecules to reprogram the protein degradation specificity of E3 ligases. By degrading proteins instead of inhibiting them, these small molecules achieve levels of functional modulation typically only possible with genetic techniques. We are inspired by this new protein degradation technology, but will take it in a new direction. Chemical damage of DNA recruits E3 ligases as well as critical DDR proteins in preparation for DNA repair. We will invent a new generation of small molecule protein degradation catalysts by repurposing these natural responses to DNA damage.
We will accomplish our goal with three aims:
Aim 1: Use DNA damage as a homing signal for induced protein degradation
Aim 2: Use direct repair of DNA damage by the repair protein MGMT to promote the degradation of other proteins
Aim 3: Promote pleiotropic protein degradation by recruiting broadly acting E3 ligases to sites of DNA damage
I propose an ambitious project that will create conceptually novel ways to study the DDR and potentially build new medicines.
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Duración del proyecto: 63 meses
Fecha Inicio: 2020-02-24
Fecha Fin: 2025-05-31
Fecha Fin: 2025-05-31
Línea de financiación: concedida
El organismo H2020 notifico la concesión del proyecto el día 2020-02-24
Línea de financiación objetivo
El proyecto se financió a través de la siguiente ayuda:
ERC-2019-COG:
ERC Consolidator Grant
Cerrada
hace 5 años
Presupuesto
El presupuesto total del proyecto asciende a
2M€
Líder del proyecto
UNIVERSITAT BASEL
No se ha especificado una descripción o un objeto social para esta compañía.
Perfil tecnológico
TRL
4-5
Perfil tecnológico
TRL
4-5
302.64K€ |
Participante