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RECOBIN-PROTACs

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Reversible Covalently Binding PROTACs Technology for Protein Degradation in Canc...

Reversible Covalently Binding PROTACs Technology for Protein Degradation in Cancer Therapy 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... ver más

31/03/2022

THE CHANCELLOR MAS...

225K€

Presupuesto del proyecto: 225K€

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THE CHANCELLOR MASTERS AND SCHOLARS OF THE UN... No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

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Financiación concedida El organismo H2020 notifico la concesión del proyecto el día 2022-03-31

MSCA-IF-2019: Individual Fellowships

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Duración del proyecto: 25 meses Fecha Inicio: 2020-02-24
Fecha Fin: 2022-03-31

Líder del proyecto

THE CHANCELLOR MASTERS AND SCHOLARS OF THE UN... No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Presupuesto del proyecto 225K€

Fecha límite de participación Sin fecha límite de participación.

Descripción del proyecto 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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