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Target5LO SIGNED

Targeting 5-lipoxygenase in the context of Acute Myeloid Leukemia

Total Cost €

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EC-Contrib. €

0

Partnership

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 Target5LO project word cloud

Explore the words cloud of the Target5LO project. It provides you a very rough idea of what is the project "Target5LO" about.

release    cells    sought    aml    forms    displaying    leukemia    entities    off    deployment    constructs    validated    il7r    linkers    model    adverse    preclinical    conjugates    foresee    myeloid    modulate    expression    pipelines    polypharmacology    applicability    showed    untargeted    therapeutic    lapachone    approved    windows    fast    treat    dozens    considering    naphthoquinone    profile    blood    biophysical    medical    accurate    programs    chemical    disease    anticancer    allosteric    implications    lipoxygenase    correlated    reactions    mouse    discontinued    toxicity    modulator    lo    biomarker    cleavable    chemistry    overcome    successful    unmet    fact    machine    site    disseminated    drug    strategies    investigation    cancers    leukaemia    conjugate    broad    disclosed    vivo    exploring    validate    imperative    dosage    fda    biology    antibody    clinical    pernicious    patients    discovery    yield    completion    drugs    lp    narrow    medicinal    synthetic    hope    acute    employing    quantitative    bioactivity    profound    efficacy    models    spatiotemporal    learning    natural    anti    cornerstone    vitro   

Project "Target5LO" 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 195˙454 €
 EC max contribution 195˙454 € (100%)
 Programme 1. H2020-EU.1.3.2. (Nurturing excellence by means of cross-border and cross-sector mobility)
 Code Call H2020-MSCA-IF-2017
 Funding Scheme MSCA-IF-EF-CAR
 Starting year 2018
 Duration (year-month-day) from 2018-03-01   to  2020-02-29

 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 195˙454.00

Map

 Project objective

Drug efficacy is cornerstone for successful drug discovery programs. Considering that, on average, FDA-approved drugs modulate dozens of off-targets it remains imperative to find strategies to overcome adverse drug reactions correlated with pernicious polypharmacology. In fact, several chemical entities displaying promising anticancer are discontinued from drug development pipelines due to narrow therapeutic windows in pre-clinical models. Here, we propose the development of antibody-drug conjugates exploring the unique bioactivity profile of the naphthoquinone natural product-lapachone (Lp) against acute myeloid leukemia (AML), an unmet medical need. Using a machine learning method, we disclosed Lp as an allosteric modulator of 5-lipoxygenase (5-LO), correlated its anticancer activity with 5-LO expression in blood cancers and showed its efficacy in a disseminated mouse model of AML.

In this project, a comprehensive investigation of novel means for the targeted delivery of Lp to leukaemia cells is sought after, considering both the promising bioactivity profile but also the significant toxicity in untargeted dosage forms. We apply state-of-the-art synthetic medicinal chemistry to design and access cleavable linkers, and site-specifically conjugate Lp to an anti-IL7R antibody, a validated biomarker in AML and other leukaemia’s. We aim at employing biophysical and chemical biology approaches to validate quantitative and fast release of Lp with accurate spatiotemporal control in in vitro disease models. Finally, we will validate the deployment of the constructs through preclinical in vivo models of AML. We foresee broad applicability of the developed technology, which may have profound implications in drug discovery. Upon successful completion of this research program, we hope to yield a new targeted drug to treat AML patients with improved efficacy and reduced side-effects.

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