Presentation on theme: "UNIVERSITA’ DEGLI STUDI DI PALERMO"— Presentation transcript:
1UNIVERSITA’ DEGLI STUDI DI PALERMO FACOLTA’ DI FARMACIADIPARTIMENTO FARMACOCHIMICO TOSSICOLOGICO E BIOLOGICODesign, synthesis and biological evaluation of new inhibitors of carcinogenic processesDott. Ilenia Abbate
2TUMOR PROGRESSIONCancer cells are less sensitive to the therapy and repopulate the tumor, facilitating tumor progressionMigratory growth factorgrowth factor-inducedmitogenesisSTAT3c-MYCPROTO-ONCOGENEPI 3 kinaseAktsurvivalRasERKMERKCyclin/cdkspromotes G1/S phase
3SIGNAL-TRANSDUCTION PATHWAYS CORRELATED TO TUMOR PROGRESSION Without fuctional HSP90, these proteins undergo proteasome-mediated degradation, leading to cell cycle arrest and apoptosis.
5Multiple HSP90 client proteins mediate acquisition and maintenance of the six properties necessary for transformation of a normal cell into a cancer cell:ability to evade apoptosisability to be self-sufficient for growthability to invade surrounding tissue and to metastasize to distant sitesability to undergo limitless replicationability to promote neoangiogenesisability not to respond to antigrowth signals.
6HSP90: molecular chaperone FoldingBiological fuctionStabilization/DegradationActivationCLIENTSPROTEINSProtein kinases (Her-2/ErbB2 e Akt)Cdk4/ciclin D complexc-Raf-1HIF-1αp53Steroid hormone receptors
7HSP90 stress condition: heat, irradiation, ROS (reactive oxygen radicals), toxins, lack of nutrients, hypoxia, bacterial and viral infections.-C-terminal domain : 10kDa, omodimerization and co-chaperones recruitment super-chaperone complex;-middle region: 35kDa, binding site for client proteins and ATPase activity;-N-terminal domain: 25kDa, binding site for ATP/ADP and inhibitors, such as geldanamycin and radicicol.
18…THANKS FOR YOUR ATTENTION DIPARTIMENTO FARMACOCHIMICO, TOSSICOLOGICO E BIOLOGICOProf. Anna Maria AlmericoProf. Antonino LauriaProf. Gaetano DattoloProf. Maria A. LivreaProf. Luisa TesoriereDott. Carla Gentile…THANKS FOR YOUR ATTENTION