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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.

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

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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