RECOBIN-PROTACs
Financiado
Reversible Covalently Binding PROTACs Technology for Protein Degradation in Canc...
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 fai...
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.
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Duración del proyecto: 25 meses
Fecha Inicio: 2020-02-24
Fecha Fin: 2022-03-31
Fecha Fin: 2022-03-31
Línea de financiación: concedida
El organismo H2020 notifico la concesión del proyecto el día 2022-03-31
Línea de financiación objetivo
El proyecto se financió a través de la siguiente ayuda:
MSCA-IF-2019:
Individual Fellowships
Cerrada
hace 5 años
Presupuesto
El presupuesto total del proyecto asciende a
225K€
Líder del proyecto
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Perfil tecnológico
TRL
4-5
Perfil tecnológico
TRL
4-5
253.84K€ |
Participante