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Content archived on 2024-05-27

Design and synthesis of selective inhibitors of human lactate dehydrogenase 5 targeting the peculiar metabolism of glucose in tumours

Objective

"Highly invasive tumour phenotypes show a metabolic switch (“Warburg effect”) from oxidative phosphorylation to an increased glycolysis. This change in glucose metabolism, in favour of a less efficient process for production of energy and anabolites, confers several advantages on the tumour cells, such as the ability to grow in poorly oxygenated conditions, which are typical of invasive hypoxic tumours. One of the key enzymes actively involved in anaerobic glycolysis, the muscle isoform of human lactate dehydrogenase (hLDH5), was shown to be overexpressed by metastatic cancer cells, and has been linked to the vitality of tumours in hypoxia. This enzyme is currently being considered as a valid target for new anticancer agents, since its inhibition leads to a cut in cancer energy supply, thus reducing its metastatic and invasive potential. A validation of hLDH5 as a safe target derives from the observation that in humans, hereditary hLDH5 deficiency causes a certain level of myopathy only after intense anaerobic exercise, whereas it does not provoke any symptoms under ordinary circumstances. This project will support a qualified international researcher in the management of a research line including molecular design and synthesis of a series of new compounds, as well as in the participation in the biological evaluation of their properties. The host institution has already discovered a suitable structural scaffold, based on N-hydroxyheterocycles (NHIs), which has furnished some efficient hLDH5-inhibitors, possessing “first-in-class” potency and isoform selectivity. This scaffold will constitute the basis for the development of larger series of optimized NHI-analogues, as well as for appropriate variations of the central NHI-scaffold, leading to completely new classes of hLDH5-inhibitors, which will constitute more suitable pre-clinical candidates for the treatment of metastatic cancer."

Fields of science (EuroSciVoc)

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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.

Call for proposal

Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.

FP7-PEOPLE-2011-IIF
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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.

MC-IIF - International Incoming Fellowships (IIF)

Coordinator

UNIVERSITA DI PISA
EU contribution
€ 193 726,80
Address
LUNGARNO PACINOTTI 43/44
56126 PISA
Italy

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Region
Centro (IT) Toscana Pisa
Activity type
Higher or Secondary Education Establishments
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Total cost

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.

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