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OBJECTIVES

LIGHTS specifically addresses early phase medicinal chemistry issues that can critically influence the time schedule for obtaining an investigational drug candidate. Nevertheless it is also expected as products of our project that potential drug candidate(s) with high quality in vitro activity profile can be obtained ready for in vivo pharmacology profiling.

In particular LIGHTS objectives are:
1. Derivation of small-ligand libraries with ligands design to bind to the Thymidylate synthase monomer /monomer interface affecting dimer formation and TS- TSmRNA interactions.
2. Validation of the integrated, multidisciplinary drug design strategy necessary to achieve objective 1, which poses a highly challenging design problem. The strategy including systems pathway studies, protein residue SH and X -labelling to identify low-affinity ligands, peptide mimetic design, and filtering for ADME properties.
3. Identification of small-ligands identified in a chemical-biology approach as effective perturbing agents to investigate the mechanism of resistance against a panel of cis-platinum resistant ovarian carcinoma cell lines.
4. Provide potential drug candidate(s) with new mechanism of action for further development as safer therapeutic agent(s) for the treatment of ovarian carcinoma.

The project is clearly oriented to directly halt the progression of ovarian cancer and interfere with the development of drug resistance upon treatment with platinum-derived drugs by inhibiting the protein regulatory function of monomeric TS.
The intermediate objectives are based on employing novel medicinal chemistry strategies to identify potential drug candidates with new mechanisms of action.



PROJECT SUMMARY

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.
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 (UK) - Naxospharma (I) - University of California San Francisco (UCSF)

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