Presentation on theme: "UNIVERSITA’ DEGLI STUDI DI PALERMO"— Presentation transcript:
1 UNIVERSITA’ DEGLI STUDI DI PALERMO FACOLTA’ DI FARMACIADIPARTIMENTO FARMACOCHIMICO TOSSICOLOGICO E BIOLOGICODesign, synthesis and biological evaluation of new inhibitors of carcinogenic processesDott. Ilenia Abbate
2 TUMOR 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
3 SIGNAL-TRANSDUCTION PATHWAYS CORRELATED TO TUMOR PROGRESSION Without fuctional HSP90, these proteins undergo proteasome-mediated degradation, leading to cell cycle arrest and apoptosis.
5 Multiple 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.
6 HSP90: molecular chaperone FoldingBiological fuctionStabilization/DegradationActivationCLIENTSPROTEINSProtein kinases (Her-2/ErbB2 e Akt)Cdk4/ciclin D complexc-Raf-1HIF-1αp53Steroid hormone receptors
7 HSP90 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