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Final Report Summary - LACTABLOCK (Design and synthesis of selective inhibitors of human lactate dehydrogenase 5 targeting the peculiar metabolism of glucose in tumours)

The purpose of this project was to train a highly qualified researcher (Dr. Reshma Rani) in managing a research line focused on the development of anti-cancer agents able to fight invasive tumours, which are normally resistant to chemotherapy and radiotherapy. The rationale of this project is based on the fact that 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 researcher, was able to efficiently carry out the molecular design and synthesis of a series of new compounds, as well as to actively participate in the biological evaluation of their properties. Each step of his formation was adequately followed by additional specialized trainers: Dr. Tiziano Tuccinardi for the molecular modelling; Prof. Gino Giannaccini, for the enzyme inhibition bioassays; Dr. Valeria Di Bussolo, for the synthesis of gluco-conjugates.
The host institution had previously discovered a suitable structural scaffold, based on Nhydroxyheterocycles (NHIs), which has furnished some efficient hLDH5-inhibitors, possessing “first-in-class” potency. This scaffold constituted 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.
Initially, Dr. Rani, who had a very strong chemical background mostly focused on organic synthesis, started to learn more about medicinal chemistry, structure-activity relationships, pharmacophoric moieties, drug-likeness, and all other concepts that are crucial for the development of new therapeutics. She then participated to an extensive literature coverage of the most modern inhibitors of hLDH5, leading to the publication of a comprehensive review which was published in an internationally renowned peer-reviewed scientific journal [Granchi C, Paterni I, Rani R, Minutolo F, “Small-molecule inhibitors of human LDH5”, Future Medicinal Chemistry 2013, Vol. 5, Issue 16, Pages 1967-1991, DOI: 10.4155/fmc.13.151].
The researcher, then, efficiently worked on the optimization of some crucial steps involved in the synthesis of NHI-based hLDH5-inhibitors, including those that were conjugated to sugar portions, thus allowing their preparation on a relatively large scale. This was particularly important since gram-scale amounts of these inhibitors were needed for further pharmacological evaluation, which were made possible by the successful synthetic advances promoted by the researcher’s work.

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