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Target5LO SIGNED

Targeting 5-lipoxygenase in the context of Acute Myeloid Leukemia

Total Cost €

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EC-Contrib. €

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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.

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

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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