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. 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 a 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. Our Consortium is clearly committed to this final aim, and the involvement of the SME Naxospharma provides expertise in discovery and synthetic chemistry support, lead development, intellectual property issues, searching for out-licensing and/or co-operative opportunities for the inventive aspects of the project.These goals will be translated into the below described objectives. Their operational goals are therein included and breakdown in the WP descriptions (sections 7 and 8). WPs also include expected deliverables, at the due time, and milestone expected results. 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 cysteine SH-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.
|Titolo:||Small ligands to interfere with Thymidylate synthase dimer formation as new tools for development of anticancer agents against ovarian carcinoma.|
|Autori:||M.P.Costi; D.Tondi; G.Ponterini; G.Marverti; M.Moruzzi; C.Frassineti; S.Ferrari; D.Guerrieri; A.Ligabue; G.Guaitoli; M.Rinaldi; D.Cardinale; A.Venturelli|
|Data di pubblicazione:||2006|
|Appare nelle tipologie:||Partecipazione a progetti di ricerca|
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