Lights EU

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		Ovarian cancer is the fifth most common cause of death from cancer in women. The standard first-line treatment is a combination of paclitaxel and carboplatin (DDP) or carboplatin alone. In the case of progressive disease or drug resistance treatment with platinum, either alone or in combination, especially investigational compounds should be used. The mechanisms behind acquired resistance to cDDP and its derivatives are not clear yet, although it is evident that the process is multifactorial including, enhanced DNA repair. In the human ovarian carcinoma cell line A2780, a 3-fold-DDP-resistance was associated with cross-resistance to the thymidylate synthase (TS) inhibitor 5-fluorouracil and to methotrexate, a 2.5-fold increase in TS, and an increase in the intracellular pools of the TS cofactor 5, 10-methylentetrahydrofolate and of tetrahydrofolate. The ultimate goal of LIGHTS is to directly halt tumour progression and the development of drug resistance upon treatment with platinum derived drugs by inhibiting the protein regulatory function of monomeric TS through small molecule cellular perturbation. The scientific and technological objectives will be to design small-ligand libraries to bind to the TS monomer (dimer interface) and thereby disrupt TS. The strategy will include, systems pathway analysis, protein SH and X -labelling to identify low-affinity ligands, peptide mimic design & synthesis, and filtering for ADME properties. The multidisciplinary approach will be carried out by a consortium integrating Molecular modelling, Chemistry, Chemoinformatics, Structural Biology and Pharmacology, and will apply the knowledge being created by genomics and other fields of basic research to the problem of discovery of anticancer agents. The consortium consists of six groups from five different countries, including three SMEs.

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	LIGands to interfere with Human TS - LIGHTS is a STREP project within the 6FP. Lights is focused on ovarian cancer and carried out by a consortium of six partners: University of Modena and Reggio Emilia (I) - University di Paris Sud (FR) European Media Laboratories (D) - Molecular Discovery (I) - Naxospharma (I) - University of California San Francisco (UCSF)
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