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UNIVERSITA’ DEGLI STUDI DI PALERMO FACOLTA’ DI FARMACIA

UNIVERSITA’ DEGLI STUDI DI PALERMO FACOLTA’ DI FARMACIA. DIPARTIMENTO FARMACOCHIMICO TOSSICOLOGICO E BIOLOGICO. Design, synthesis and biological evaluation of new inhibitors of carcinogenic processes. Dott. Ilenia Abbate. TUMOR PROGRESSION.

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UNIVERSITA’ DEGLI STUDI DI PALERMO FACOLTA’ DI FARMACIA

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  1. UNIVERSITA’ DEGLI STUDI DI PALERMO FACOLTA’ DI FARMACIA DIPARTIMENTO FARMACOCHIMICO TOSSICOLOGICO E BIOLOGICO Design, synthesis and biological evaluation of new inhibitors of carcinogenic processes Dott. Ilenia Abbate

  2. TUMOR PROGRESSION Cancer cells are less sensitive to the therapy and repopulate the tumor, facilitating tumor progression Migratorygrowthfactor growthfactor- induced mitogenesis STAT3 c-MYC PROTO-ONCOGENE PI 3 kinase Akt survival Ras ERK MERK Cyclin/cdks promotes 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.

  4. …andSignalingPathways • HSP90 chaperone • stabilizes oncoproteins • Inhibiting HSP90 degrades • oncoproteins, stopping tumor growth

  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 apoptosis • ability to be self-sufficient for growth • ability to invade surrounding tissue and to metastasize to distant sites • ability to undergo limitless replication • ability to promote neoangiogenesis • ability not to respond to antigrowth signals.

  6. HSP90: molecularchaperone CLIENTS PROTEINS • Folding • Biologicalfuction • Stabilization/Degradation • Activation • Protein kinases (Her-2/ErbB2 e Akt) • Cdk4/ciclin D complex • c-Raf-1 • HIF-1α • p53 • Steroid 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.

  8. INHIBITORS HSP90

  9. BINDING PROTEIN… geldanamycin H-BOND ACCEPTORS/DONORS: Asp51, Asp54, Lys58, Asp93, Gly97, Lys112, Phe139,Thr184 HYDROPHOBIC INTERACTION: Leu48, Lys58, Met98, Thr109, Val136, Phe138, Val150, Val186

  10. HSP90 INHIBITORS ZINC DATABASE 5,627,809 compounds PYRAZOLES 28 SULFONAMIDES 9 PURINES 12 Lipinsky’s Rule PU1 PU2 PI1 PI2 SU1 SU2 Molecular Docking HTVS Glide level MolecolareDocking SP Glide level HYPO1 HYPO2 MOLECULAR DOCKING/ PHARMACOPHORE APPROACH MATCHING HITS 112 COMPOUNDS

  11. 112 DERIVATIVES

  12. SYNTHESIS dihydropyrazole9 and 2-amino-3-cyanopyridine 10 a: R1=Cl, R2=R3=H b: R1=R2=H, R3=NMe2 c: R1=R3=H, R2=F d:R1=OCH3, R2=R3=H e: R1=H, R2=R3=OCH3 f: R1=R2=H,R3=OCH3 g: R1=R2=H, R3=OH h: R1=OH, R2=OCH3, R3=H i: R1=R3=H, R2=OCH3 j:R1=R2=H, R3=NEt2 k: R1=Br, R2=R3=H

  13. pyridinothieno/benzothieno-triazolO-pyrimidines R=CN, Ph X= CH, N

  14. BIOLOGICAL SCREENING NATIONAL CANCER INSTITUTE, Bethesda DEVELOPMENTAL THERAPEUTIC PROGRAM

  15. NATIONAL CANCER INSTITUTE DEVELOPMENTAL THERAPEUTICS PROGRAM MEAN GRAPH AND DOSE RESPONSE CURVES 16 side chain O LEUKEMIA RENAL CANCER CNS CANCER SN-12C:pGI50=7.96 SF-539:pGI50=7.69 K-562:pGI50=7.64

  16. MEAN GRAPH One DOSE RESPONSE CURVES 60 cell lines single dose of 10 uM

  17. HSP90 CLIENT PROTEIN • c-Kit • EGFR / C-met • AR / p-Akt • HER2 / ER • b-Raf (V800E) • TUMOR • GIST • NSCLC • PROSTATE (PTEN-/-) • BREAST (HER2 +) • MELANOMA

  18. DIPARTIMENTO FARMACOCHIMICO, TOSSICOLOGICO E BIOLOGICO • Prof. Anna Maria Almerico • Prof. Antonino Lauria • Prof. Gaetano Dattolo • Prof. Maria A. Livrea • Prof. Luisa Tesoriere • Dott. Carla Gentile …THANKS FOR YOUR ATTENTION

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