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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.

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

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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