Obiettivo In cancer, progression from a normal to a fully tumourigenic phenotype involves the accumulation of mutations in genes, which control cell function. Since the acquisition of each tumour cell phenotype (immortalisation, transformation and metastasis) is associated with distinct sets of mutations, targeting mutated gene products that confer each of these tumour-specific phenotypes should be a good anti-cancer strategy. The successful treatment of cancer will require the availability of suitable therapeutic substances against a significant number of targets. We will study targets that we have identified as being very suitable. We will also attempt to identify new targets in areas where suitable therapies are lacking.This proposal brings together groups with a very high level of expertise in structural biology, screening and design to find suitable lead molecules, as well as in identification and validation of both targets and leads using mammalian genetics and mouse gene "knock-outs". The studies of the different targets that we propose will, if successful, lay the foundation for exploitation in a full scale effort in medicinal chemistry and pharmaceutical drug discovery.Description of the workIn this proposal we will extend our previous studies of key targets in the Rb/p53 biochemical pathways that are controlled by the cyclin D-dependent kinases and the p19ARF/Mdm2/p53 interaction. We will investigate a number of new pathways that are controlled by Ras- and Rho-family small G proteins, with an emphasis on targets that might be important in preventing metastasis and invasion. In parallel, we will attempt to identify new targets using retroviral screening technologies and we will also further study the Ras -> Ral cascade and RhoA-induced apoptosis and transformation.A major aim will be to learn how to most effectively inhibit protein-protein interactions. We will combine site-directed mutagenesis with studies of the energetics, with a view to understanding, and possibly ultimately being able to predict, which regions are best targeted. We will combine computational and experimental approaches, using NMR spectroscopy, to design suitable molecules that might interact tightly and specifically with flatter protein surfaces. In parallel, we will develop new methodology to extend the NMR method to larger proteins and complexes by encapsulating them in reverse micelles formed in low viscosity solvents. Finally, we will develop new in vivo assays to find inhibitors of protein-protein interactions.Milestones and expected resultsWe will attempt to identify small molecules, typically peptides that have a desired inhibitory function, e.g. of a kinase or of a particular protein-protein interaction. Together with the structures that we determine, such peptides will be used to further validate targets and will provide initial information for the rational design of non-peptide leads for exploitation in full scale drug discovery. Our studies of protein-protein interactions, when taken together, should considerably enhance our knowledge of whether and how it will be possible to attack these traditionally more difficult targets. Campo scientifico medical and health sciencesbasic medicinepharmacology and pharmacydrug discoverynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomicsmedical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsnatural sciencesbiological sciencesgeneticsmutationmedical and health sciencesclinical medicineoncology Programma(i) FP5-LIFE QUALITY - Specific Programme for research, technological development and demonstration on "Quality of life and management of living resources", 1998-2002 Argomento(i) 1.1.1.-3. - Key action The "Cell factory" Invito a presentare proposte Data not available Meccanismo di finanziamento CSC - Cost-sharing contracts Coordinatore THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE Contributo UE Nessun dato Indirizzo 80,Tennis Court Road, 80 CB2 1GA CAMBRIDGE Regno Unito Mostra sulla mappa Costo totale Nessun dato Partecipanti (10) Classifica in ordine alfabetico Classifica per Contributo UE Espandi tutto Riduci tutto CANCER RESEARCH TECHNOLOGY LIMITED Regno Unito Contributo UE Nessun dato Indirizzo Sardinia House, Sardinia Street WC2A 3NL LONDON Mostra sulla mappa Costo totale Nessun dato CONSEJO SUPERIOR DE INVESTIGACIONES CIENTIFICAS Spagna Contributo UE Nessun dato Indirizzo Calle Serrano 117 MADRID Mostra sulla mappa Collegamenti Sito web Opens in new window Costo totale Nessun dato FUNDACION CENTRO NACIONAL DE INVESTIGACIONES ONCOLOGICAS CARLOS III Spagna Contributo UE Nessun dato Indirizzo Ctra. 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