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Geldanamycin: A Novel Approach to Treating Cancer Elisabeth von Moos December 1, 2005
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2 More than 100 different and distinct diseases. What is Cancer? Group of diseases characterized by the uncontrolled growth of cells or the failure of cells to die normally. An estimated 149,000 new cases of cancer will be diagnosed in Canada in 2005. 38% of Canadian women and 44% of Canadian men will develop cancer during their lifetimes.
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3 Chemotherapy Current Cancer Therapies Surgery Radiation therapy Biological therapy Photodynamic therapy Targeted cancer therapy Many cancers have no cure. Poor prognosis for patients with solid tumors.
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4 Important Therapeutic Targets Therapy Mutant p53 HIF-1 ErbB2 V-Src Akt Raf-1 Bcr-Abl Soluble kinases Transmembrane kinases Transcription factors Neckers, N. Trends Mol. Med. 2002, 8, S55. Steroid receptors PR, AR, GCR
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5 Heat Shock Protein 90 Hsp90 Mutant p53 HIF-1 ErbB2 V-Src Akt Raf-1 Bcr-Abl Soluble kinases Transmembrane kinases Transcription factors Neckers, N. Trends Mol. Med. 2002, 8, S55. Steroid receptors PR, AR, GCR
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6 Heat Shock Proteins Prevent protein aggregation Intracellular protein transport Fold nascent proteins or repair misfolded proteins Repair denatured proteins Control regulatory proteins Degrade denatured proteins
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7 Central Dogma of Molecular Biology DNA RNA Protein Transcription Translation
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8 Molecular Chaperones nascent protein mature protein ATP ADP + P i
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9 Heat Shock Proteins Protect Cells stress Denatured proteins detected Heat shock proteins produced Denatured proteins refolded Stress denatures proteins
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10 Heat Shock Protein 90 One of the most abundant cellular proteins Functions in a multi- component complex Captures and holds client proteins in intermediate states of folding ATP-dependant Prodromou, C. Nature Struct. Biol. 1997, 4, 477. ATP
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11 One of the most abundant cellular proteins Functions in a multi- component complex Captures and holds client proteins in intermediate states of folding ATP-dependant Heat Shock Protein 90 Prodromou, C. Nature Struct. Biol. 1997, 4, 477. ADP
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12 Mechanism of Action of Hsp90 Isaacs, J.S. Cancer Cell, 2003, 3, 213. Proteosome client Hip Hsp70 Hsp40 p60Hop BAG-1 PP5 ImmunoP’s p23 Cyp40 p50Cdc37 ADPATP ATP hydrolysis ATP exchange unfolded folded
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13 The Ansamycin Antibiotics
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14 Geldanamycin DeBoer, C. et al. J. Antibiot. 1970, 33, 781. Merrell, P.H. et al. J. Am. Chem. Soc. 1970, 92, 7591. Isolated in 1970 fromStreptomyces hygroscopicus Shows anti-microbial, anti-viral, and anti-tumor activity
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15 Macbecin 1 Tanida, S. et al. J. Antibiot. 1980, 33, 199. Muroi, M. et al. Tetrahedron, 1981, 37, 1123. Isolated in 1980 from Nocardia Shows anti-microbial, anti-viral, and anti-tumor activity
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16 Herbimycin A Tanida, S. et al. J. Antibiot. 1980, 33, 199. Muroi, M. et al.Tetrahedron, 1981, 37, 1123. Isolated in 1980 from Nocardia Shows anti-microbial, anti-viral, and anti-tumor activity
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17 Herbimycin A – Tatsuta Synthesis Tatsuta, K. et al. Tetrahedron Lett. 1991, 32, 6015. 15 16 3 4 15 4
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18 Herbimycin A – Martin Synthesis Martin, S.F. et al. Tetrahedron, 1999, 55, 3561. 16 15 2 3 8 9 8 9 3 3 9 8
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19 Macbecin 1 – Evans Synthesis Evans, D.A. et al. J. Org. Chem. 1993, 57, 1067. 12 13 4 5 12 13 5 4
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20 Macbecin 1 – Panek Synthesis Panek, J.S; Xu, F. J. Am. Chem. Soc. 1995, 117, 19587. 14 10 5 5 14 10 5
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21 Geldanamycin – Andrus Synthesis Andrus M.B. et al. Org. Lett. 2002, 4, 3549. 2 2 14
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22 Geldanamycin Synthesis
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23 Geldanamycin Synthesis
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24 Geldanamycin Synthesis
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25 Synthesis of Pyrone
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26 Geldanamycin Synthesis
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27 Geldanamycin Synthesis
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28 Geldanamycin Synthesis
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29 Geldanamycin Synthesis
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30 Geldanamycin Synthesis
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31 Geldanamycin Synthesis
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32 Geldanamycin Synthesis
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33 Geldanamycin Synthesis
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34 Geldanamycin Synthesis
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35 Evaluation of Geldanamycin as a Possible Anti-Cancer Drug Cancer cell proliferation Tyrosine kinase
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36 Geldanamycin Binds a Specific Protein Whitesell, L. et al. Proc. Natl. Acad. Sci. 1994, 91, 8324. Agarose Bead Geldanamycin
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37 Cell Lysis to Obtain Cellular Contents Cell lysis Lysate obtained for study Whitesell, L. et al. Proc. Natl. Acad. Sci. 1994, 91, 8324.
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38 Geldanamycin Binds a Specific Protein Agarose Bead Geldanamycin Whitesell, L. et al. Proc. Natl. Acad. Sci. 1994, 91, 8324.
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39 Cells Incubated with Geldanamycin Cell lysis Cells exposed to geldanamycin Lysate obtained for study Whitesell, L. et al. Proc. Natl. Acad. Sci. 1994, 91, 8324.
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40 Geldamycin Binding Occurs in vivo Agarose Bead Geldanamycin Lysate incubated with GA-coupled beads Whitesell, L. et al. Proc. Natl. Acad. Sci. 1994, 91, 8324.
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41 Immunoblotting control Hsp90 monoclonal antibody added Whitesell, L. et al. Proc. Natl. Acad. Sci. 1994, 91, 8324. Hsp90 Protein eluted from GA-coupled beads
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42 Metabolic Labelling of Protein Cell lysis Cells “fed” methionine containing 35 S Protein labelled with 35 S Lysate obtained for study Whitesell, L. et al. Proc. Natl. Acad. Sci. 1994, 91, 8324.
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43 Radiolabelling Cell lysate was incubated with GA-coupled beads Whitesell, L. et al. Proc. Natl. Acad. Sci. 1994, 91, 8324.
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44 1 2 Major cellular protein 3 After heat shock Radiolabelling 1 2 3 Whitesell, L. et al. Proc. Natl. Acad. Sci. 1994, 91, 8324. SDS-PAGE
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45 Proteolytic Digestion SDS-PAGE RESULT: all bands represent the same protein V8 Proteins were partially digested with V8 proteolytic enzyme = Whitesell, L. et al. Proc. Natl. Acad. Sci. 1994, 91, 8324. RESULT: Geldnamycin binds heat shock protein 90 1 2 3
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46 Preclinical Studies of Geldanamycin Anti-Tumor Activity Hepatotoxicity Supko, J.G. et al. Cancer Chemo. Pharmacol. 1995, 36, 305.
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47 Structure Activity Relationship 19-substituents not tolerated Schnur, R.C. et al. J. Med. Chem. 1995, 38, 3806.
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48 Structure Activity Relationship Bicyclic and tricyclic quinones were active 19-substituents not tolerated Schnur, R.C. et al. J. Med. Chem.1995, 38, 3806. 19
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49 Structure Activity Relationship Small alkylamino groups: - unfunctionalized - bearing hydroxy or amino groups Schnur, R.C. et al. J. Med. Chem.1995, 38, 3806. 19-substituents not tolerated Bicyclic and tricyclic quinones were active 19 17
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50 Structure Activity Relationship 17AAG: 17-(allylamino)-17-demethoxygeldanamycin Schnur, R.C. et al. J. Med. Chem. 1995, 38, 3813. Carbamate and 2,3-double bond essential for activity 17 2 3
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51 17AAG potential limitations: Limited solubility Cumbersome formulation Dose and schedule dependant liver toxicity PHASE 2 Clinical Trials of 17AAG Prolonged disease stabilization Cytostatic drug effect PHASE 1 Dose recommendations were made
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52 Genetic Plasticity of Cancer Cells Hsp90 Mutant p53 HIF-1 ErbB2 V-Src Akt Raf-1 Bcr-Abl Soluble kinases Transmembrane kinases Transcription factors Neckers, N. Trends Mol. Med. 2002, 8, S55. Steroid receptors PR, AR, GCR
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53 Benign mutation Normal Protein Function Lethal mutation Cell Death Hsp90 Safeguards Against Mutations Normal Protein Synthesis Faulty Protein Synthesis Neckers, L. et al. Proc. Natl. Acad. Sci. 1996, 93, 8379. mutant p53
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54 Specificity of Hsp90 Inhibitors 17AAG has up to 100x higher affinity for tumor cells as compared to normal cells. Hsp90 is abundantly expressed in both normal and tumor cells. normal celltumor cell constitutively expressed WHY? normal celltumor cell Kamal, A. et al. Nature 2003, 425, 407.
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55 Future Work Improved pharmacological and toxicity profiles Llauger, L. et al. J. Med. Chem. 2005, 48, 2892. Whitesell, L.; Lindquist, S.L. Nature Rev. Cancer 2005, 5, 761. Roe, S.M. et al. J. Med. Chem. 1999, 42, 260. 17AAG Radiation therapy Chemotherapy Immunotherapy Novel Hsp90 Inhibitors Combination Therapy + Conformation of Hsp90-bound geldanamycin
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56 Summary Hsp90 inhibitors are a novel class of anti-cancer drugs. Geldanamycin has important functions as a chemical probe. SAR studies led to 17AAG – phase 2 clinical trials. Novel Hsp90 inhibitors are currently being developed.
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57 Acknowledgements Dr. Robert Ben Vincent Bouvet Frank Cease Jenn Chaytor Pawel Czechura Jessica Jackman Nicole Le Grand Aleks Paliga Suhuai Liu Roger Tam Indira Thapa
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