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UNIVERSITA DEGLI STUDI DI PALERMO FACOLTA DI FARMACIA Design, synthesis and biological evaluation of new inhibitors of carcinogenic processes DIPARTIMENTO.

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Presentation on theme: "UNIVERSITA DEGLI STUDI DI PALERMO FACOLTA DI FARMACIA Design, synthesis and biological evaluation of new inhibitors of carcinogenic processes DIPARTIMENTO."— Presentation transcript:

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

2 2 Cancer cells are less sensitive to the therapy and repopulate the tumor, facilitating tumor progression Migratory growth factor PROTO-ONCOGENEPROTO-ONCOGENE STAT3 c-MYC growth factor- inducedmitogenesis Ras ERK MERK Cyclin/cdks promotes G1/S phase PI 3 kinase Akt survival

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 4 HSP90 chaperone stabilizes oncoproteins Inhibiting HSP90 degrades oncoproteins, stopping tumor growth

5 5 ability to evade apoptosis ability to be self-sufficient for growth ability to invade surrounding tissue and to metastasize to distant sites 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 undergo limitless replication ability to promote neoangiogenesis ability not to respond to antigrowth signals.

6 Folding Biological fuction Stabilization/Degradation Activation Folding Biological fuction Stabilization/Degradation Activation CLIENTS PROTEINS 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.

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

10 PURINES 12 PYRAZOLES 28 SULFONAMIDES 9 HSP90 INHIBITORS PU 1 PU 2 PI 1 PI 2 SU 1 SU 2 HYPO1 HYPO2 ZINC DATABASE 5,627,809 compounds Lipinskys Rule Molecular Docking HTVS Glide level MolecolareDocking SP Glide level MATCHING HITS MOLECULAR DOCKING/ PHARMACOPHORE APPROACH MOLECULAR DOCKING/ PHARMACOPHORE APPROACH

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12 a: R 1 =Cl, R 2 =R 3 =H b: R 1 =R 2 =H, R 3 =NMe 2 c: R 1 =R 3 =H, R 2 =F d: R 1 =OCH 3, R 2 =R 3 =H e: R 1 =H, R 2 =R 3 =OCH 3 f: R 1 =R 2 =H, R 3 =OCH 3 g: R 1 =R 2 =H, R 3 =OH h: R 1 =OH, R 2 =OCH 3, R 3 =H i: R 1 =R 3 =H, R 2 =OCH 3 j: R 1 =R 2 =H, R 3 =NEt 2 k: R 1 =Br, R 2 =R 3 =H

13 R=CN, Ph X= CH, N R

14 NATIONAL CANCER INSTITUTE, Bethesda DEVELOPMENTAL THERAPEUTIC PROGRAM

15 15 K-562:pGI 50 =7.64 LEUKEMIA CNS CANCER SF-539:pGI 50 =7.69 RENAL CANCER SN-12C:pGI 50 = side chain O

16 16 60 cell lines single dose of 10 uM

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

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


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