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RECOBIN-PROTACs SIGNED

Reversible Covalently Binding PROTACs Technology for Protein Degradation in Cancer Therapy

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EC-Contrib. €

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 RECOBIN-PROTACs project word cloud

Explore the words cloud of the RECOBIN-PROTACs project. It provides you a very rough idea of what is the project "RECOBIN-PROTACs" about.

technique    bet    proximity    functional    causing    proteolysis    library    modification    poor    acute    molecules    proximal    e3    rational    protease    stability    affinity    cysteine    modalities    protac    cancer    reactive    labeling    tools    receives    masked    recobin    efficient    off    leukemia    connected    active    aggressive    reversible    proliferation    today    binding    cells    stable    therapies    discovery    specificity    aml    stabilizing    labile    blood    residue    consists    chimeras    conjugates    flexible    lines    ligase    intervention    inhibition    protacs    uses    modern    disease    handle    bone    medicine    therapeutic    immolative    site    enzyme    drug    small    inhibit    release    chemoselective    myeloid    ligands    interactions    ligand    healthy    permeability    protein    antibody    molecule    conjugated    covalently    cell    lys    linker    lack    degraders    forms    group    covalent    inside    degradation    ternary    marrow    limit    rt53    selectively    proteins    generate    enhances    linkers    cleavage    utility    synthesis    self    connects    tested    concentrations   

Project "RECOBIN-PROTACs" data sheet

The following table provides information about the project.

Coordinator
THE CHANCELLOR MASTERS AND SCHOLARSOF THE UNIVERSITY OF CAMBRIDGE 

Organization address
address: TRINITY LANE THE OLD SCHOOLS
city: CAMBRIDGE
postcode: CB2 1TN
website: www.cam.ac.uk

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
fax: n.a.

 Coordinator Country United Kingdom [UK]
 Total cost 224˙933 €
 EC max contribution 224˙933 € (100%)
 Programme 1. H2020-EU.1.3.2. (Nurturing excellence by means of cross-border and cross-sector mobility)
 Code Call H2020-MSCA-IF-2019
 Funding Scheme MSCA-IF-EF-ST
 Starting year 2020
 Duration (year-month-day) from 2020-04-01   to  2022-03-31

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    THE CHANCELLOR MASTERS AND SCHOLARSOF THE UNIVERSITY OF CAMBRIDGE UK (CAMBRIDGE) coordinator 224˙933.00

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 Project objective

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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