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.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- medical and health sciences basic medicine pharmacology and pharmacy drug discovery
- medical and health sciences basic medicine medicinal chemistry
- medical and health sciences clinical medicine oncology leukemia
- medical and health sciences basic medicine pharmacology and pharmacy adverse drug reactions
- natural sciences computer and information sciences artificial intelligence machine learning
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Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions
MAIN PROGRAMME
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H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility
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Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
MSCA-IF-EF-CAR - CAR – Career Restart panel
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Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) H2020-MSCA-IF-2017
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Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.
CB2 1TN CAMBRIDGE
United Kingdom
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.