The purpose of this research project is the development of preclinical anti-cancer drug candidates able to fight hypoxic solid tumours, which are normally resistant to chemotherapy and radiotherapy. Highly invasive tumour cells are characterized by a metabolic switch, known as the Warburg effect, from “normal” oxidative phosphorylation to an increased anaerobic glycolysis. This ensures a sufficient energy supply from glucose, even in hypoxic environments. One of the key enzymes involved in anaerobic glycolisis, the muscle isoform of lactate dehydrogenase (LDH5), has been recently shown to be overexpressed by metastatic cancer cells, and has been linked to the vitality of tumours in hypoxia. This enzyme may be considered as a valid target for new anticancer agents, since its inhibition would lead to a cut in cancer energy supply, thus reducing its metastatic and invasive potential. A validation of LDH5 as a safe target derives from the observation that in humans, hereditary LDH5 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. Each step of his formation will be adequately followed by additional specialized trainers. The host institution has already identified a suitable structural scaffold, based on N-hydroxyheterocycles, which has furnished some preliminary LDH5 inhibitors, comparable to those observed with the few examples known in literature. This scaffold constitutes the basis for the development of a large series of analogues, and thus it increases the chances of finding highly active new LDH5 inhibitors, which will constitute pre-clinical candidates for the treatment of metastatic cancer.
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