PRECIOUS METALS,
DIAMONDS & GEMSTONES
INVESTMENT SUMMIT
                2.40 – 3.05
                Metals in Medicine - P...
Metals in Medicine -
PGMs in anticancer treatments


       Peter J. Sadler FRS
     Professor of Chemistry
      Universi...
A Periodic Table
                of Medicines                               He
                                          B...
Metals in Medicine-
PGMs in anticancer treatments


   • Excited-state Platinum

   • Organo-PGMs
   - Ruthenium
   - Irid...
Prof Peter Sadler’s Group > 30 years experience
Track record of patents/commercial development

• Pt radiosensitization ag...
Major Unmet Medical Need
• Cytotoxics (drugs that kill cells) market
  segment that includes platinum-based
  therapeutics...
Barnett Rosenberg
             1961 Professor of Biophysics
             Michigan State University




    +         -



...
Effect of electric fields on cell growth

“Inert” Pt
electrodes



   Growth medium      E. coli   + cis- [PtCl2(NH3)2]
  ...
Platinum treatment

Bob Champion MBE          Lance Armstrong




                         1996 diagnosed with
1979 diagno...
Carboplatin           Picoplatin
                         Phase III
   FDA Approval          Colorectal Metastatic
   1989...
Clinically Approved Platinum
        Anticancer Compounds
            H3N
                                    Carboplatin
...
Rh          Prices of
                                       2600         platinum
Platinum group metals
                 ...
Photochemotherapy


 Activation by light


  Directed therapy
  Destroys the cancer cells
  Less side-effects
Photochemotherapy



       Laser

                    Cancer
                      cell



 Drug Activation
Human Ovarian Cancer Cells
                                                   Dark
IC50         >288            >288
μM
  ...
Human Ovarian Cancer Cells

IC50                                    Light Dark
             >288            >288
μM
      ...
Potent photoactivated
                                           platinum anticancer
                                     ...
Human bladder cancer cells

       +100 µM Pt (dark)                            +100 µM Pt (light)

     50 µm            ...
Human bladder cancer cells




  25 µM        50 µM       100 µM




DAPI Fluorescence: stains duplex DNA
  Cell shrinkage...
Organo-PGMs
       • Seat coated
         with carbon




• Reactive                 Cisplatin
  leg(s)               Diff...
Ru(II) Arene Anticancer Complexes

                   R
                                              η6-arene



        ...
Ru(II) Arene Anticancer Complexes

                   R
                                              η6-arene

  Tether
 ...
Tuning the activity
of osmium compounds     IC50(µM)
                                50

                                4...
Tuning the activity
of osmium compounds     IC50(µM)
                                  50

                               ...
Tuning the activity
of osmium compounds     IC50(µM)
                                 50

                                ...
Tuning the reactivity of osmium complexes
                                       Reaction   DNA                       Dose...
Tuning the reactivity of osmium complexes
                                       Reaction   DNA                       Dose...
Anticancer Organo-PGMs




Novel DNA interactions
Organo-osmium in
        ovarian cancer cell




New target sites: new mechanism of action
Opportunities
• Activity in human cancer cell lines
  comparable to or better than cisplatin
• Different mechanism of acti...
Next Steps
                • Structure-activity relationships
   University

                • Mechanism of cancer cell cy...
Historic License Deals
• University deal values are often not disclosed
• May 2009 - Sanofi-Aventis will pay Exelixis up f...
Advances in PGM Anticancer Agents


     • Excited-state
       Platinum
                                                 ...
Acknowledgements




• University of Warwick   • ICT Biosciences, Bradford
• University of Dundee/   • Czech Academy of Sc...
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Objective Capital Precious Metals, Diamonds and Gemstones Investment Summit: Metals in Medicine - PGMs in anti-cancer treatments - Peter Sadler

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Objective Capital Precious Metals, Diamonds and Gemstones Investment Summit
Metals in Medicine - PGMs in anti-cancer treatments
20 May 2010
by Prof Peter Sadler - University of Warwick

Published in: Economy & Finance, Business
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Objective Capital Precious Metals, Diamonds and Gemstones Investment Summit: Metals in Medicine - PGMs in anti-cancer treatments - Peter Sadler

  1. 1. PRECIOUS METALS, DIAMONDS & GEMSTONES INVESTMENT SUMMIT 2.40 – 3.05 Metals in Medicine - PGMs in anti-cancer treatments Prof Peter Sadler – Professor of Chemistry, University of Warwick THE LONDON CHAMBER OF COMMERCE AND INDUSTRY ● THURSDAY, 20 MAY 2010 www.ObjectiveCapitalConferences.com
  2. 2. Metals in Medicine - PGMs in anticancer treatments Peter J. Sadler FRS Professor of Chemistry University of Warwick
  3. 3. A Periodic Table of Medicines He B LiLiBe B C Ne NO F Mg Al Ar Ti Cr Fe S Cl Sc Ti Cr Cu Ga Ge As2O Br Kr Al N Na V Mn Zn Si P Rb Sr Y Zr Nb Ru Rh Pd Ag Cd In Sb Te Xe K Co 67Ga Ca Cs Ba La Hf Ta W Re Os Ir Pt Au Hg Tl Pb Bi Se 90Y Mo 99m Sn Br Sedoneural Sr Tc Ag As I 188Re Cs La Ce153 Nd Gd Sm Eu Gd Tb Dy Ho Er Sb Yb Lu Pr Tm Sm 201Tl Ba Pt Au Bi 133Xe La
  4. 4. Metals in Medicine- PGMs in anticancer treatments • Excited-state Platinum • Organo-PGMs - Ruthenium - Iridium - Osmium
  5. 5. Prof Peter Sadler’s Group > 30 years experience Track record of patents/commercial development • Pt radiosensitization agents (M&B/Rhône Poulenc) • Gold anticancer compounds (SmithKlineFrench - preclinical development) • Photactivated Pt anticancer agents (Scottish Enterprise/ Univ Dundee/MRC/EPSRC/ERC) • Organometallic Ru anticancer (Ru: Edinburgh Technology Fund/MMI/Oncosense - preclinical development) • Organometallic Os and Ir anticancer (HEIF/EPSRC)
  6. 6. Major Unmet Medical Need • Cytotoxics (drugs that kill cells) market segment that includes platinum-based therapeutics excluding monoclonal antibodies • US $6b (12.5%) of the cancer market in 2006 – Breast, lung, colorectal and ovarian cancers • 5-year survival rates – 40-60% for colorectal cancer – 35-38% ovarian cancer • No one effective treatment for many cancers
  7. 7. Barnett Rosenberg 1961 Professor of Biophysics Michigan State University + - Electric field lines Mitotic spindle for equal and opposite formation point charges during division of (electric dipole) a eukaryotic cell
  8. 8. Effect of electric fields on cell growth “Inert” Pt electrodes Growth medium E. coli + cis- [PtCl2(NH3)2] (NH4Cl) cisplatin Cisplatin approved by FDA 1978 1844 Peyrone's chloride
  9. 9. Platinum treatment Bob Champion MBE Lance Armstrong 1996 diagnosed with 1979 diagnosed with testicular cancer testicular cancer Won Tour de France 1981 won the each year from Grand National 1999 to 2005
  10. 10. Carboplatin Picoplatin Phase III FDA Approval Colorectal Metastatic 1989 Cancer Structure: Structure: S.Neidle, I.M. Ismail, Y. Chen, Z. Guo, P.J. Sadler S. Parsons, P.J. Sadler J. Inorg. Biochem. Chem. Eur. J. 1980 13 , 205-212. 1998, 4, 672-676.
  11. 11. Clinically Approved Platinum Anticancer Compounds H3N Carboplatin Cl Pt $673m 2004 H3N Cl Cisplatin $100m 1999 Oxaliplatin $1.9b 2006 Drawbacks $3.4b 2012 • Acquired or inherent resistance • Toxic side effects
  12. 12. Rh Prices of 2600 platinum Platinum group metals group metals Pt Global Oxaliplatin 1610 $48,000M $1,900M (2006) (2006) Carboplatin $673M (2004) Pd Ir Cisplatin 483 Os 510 $100M Platinum (1999) Ru 380 ca. 6% 190 Cancer market Platinum sales US Dollars per troy oz (31.1 g) [04/10]
  13. 13. Photochemotherapy Activation by light Directed therapy Destroys the cancer cells Less side-effects
  14. 14. Photochemotherapy Laser Cancer cell Drug Activation
  15. 15. Human Ovarian Cancer Cells Dark IC50 >288 >288 μM N3 OH NH3 >244 200 Pt 152 H3N N3 OH OH H3N N3 Pt H3N Cl 100 OH N3 Pt H3N N3 N OH H3N Cl Pt H3N N3 OH
  16. 16. Human Ovarian Cancer Cells IC50 Light Dark >288 >288 μM N3 OH NH3 >244 200 Pt 152 133 H3N OH N3 151 OH H3N N3 99 Pt H3N Cl 100 OH N3 Pt H3N N3 N OH H3N Cl Pt H3N OH N3 2
  17. 17. Potent photoactivated platinum anticancer compound 100 Light Dark Viable Cells 50 (%) Cisplatin 0 1 10 100 µM Mackay, Woods, Heringová, Kaspárková, Pizarro, Moggach, Parsons, Brabec, Sadler PNAS 2007, 104, 20743-20748.
  18. 18. Human bladder cancer cells +100 µM Pt (dark) +100 µM Pt (light) 50 µm 50 µm Rapid rounding, “ballooning” of cells in light [Bednarski, Grünert, Zielzki, Wellner, Mackay, Sadler, Chemistry & Biology, 2006, 13, 61-67]
  19. 19. Human bladder cancer cells 25 µM 50 µM 100 µM DAPI Fluorescence: stains duplex DNA Cell shrinkage, loss of contact, nuclear packing and loss of nucleus
  20. 20. Organo-PGMs • Seat coated with carbon • Reactive Cisplatin leg(s) Different shape
  21. 21. Ru(II) Arene Anticancer Complexes R η6-arene Ru Z X Leaving Y Group(s) Yan, Melchart, Habtemariam, Sadler Chem. Commun. 2005, 4764 – 4776 Dougan, Sadler Chimia , 2007, 61, 704-715
  22. 22. Ru(II) Arene Anticancer Complexes R η6-arene Tether Ru Z X Chelated Leaving Y Ligand Group(s) Yan, Melchart, Habtemariam, Sadler Chem. Commun. 2005, 4764 – 4776 Dougan, Sadler Chimia , 2007, 61, 704-715
  23. 23. Tuning the activity of osmium compounds IC50(µM) 50 40 30 Inactive 20 10 Human ovarian cancer cells
  24. 24. Tuning the activity of osmium compounds IC50(µM) 50 40 30 active 20 As active as Cisplatin 10 Human ovarian cancer cells
  25. 25. Tuning the activity of osmium compounds IC50(µM) 50 40 I 30 highly active 20 10x more 10 Active than Cisplatin Human ovarian cancer cells
  26. 26. Tuning the reactivity of osmium complexes Reaction DNA Dose (hours) binding% (µM) 5 100 50 4 80 40 3 60 30 Weak Slow Non-toxic binding 2 40 20 1 20 10 Human ovarian cancer cells van Rijt, Peacock, Johnstone, Parsons, Sadler, Inorg. Chem., 2009, 48 , 1753-62
  27. 27. Tuning the reactivity of osmium complexes Reaction DNA Dose (hours) binding% (µM) 5 100 50 4 80 40 3 60 30 Strong Fast Active binding 2 40 20 1 20 10 Human ovarian cancer cells van Rijt, Peacock, Johnstone, Parsons, Sadler, Inorg. Chem., 2009, 48 , 1753-62
  28. 28. Anticancer Organo-PGMs Novel DNA interactions
  29. 29. Organo-osmium in ovarian cancer cell New target sites: new mechanism of action
  30. 30. Opportunities • Activity in human cancer cell lines comparable to or better than cisplatin • Different mechanism of action : activity against cisplatin-resistant cells • Potentially less severe side-effects • Easy synthesis, high yields and lower cost • Potential for combination therapy
  31. 31. Next Steps • Structure-activity relationships University • Mechanism of cancer cell cytotoxicity including cell uptake • Activity of lead compounds in well-established in vivo cancer models Collaboration Grants for • Establish a panel of 6 lead compounds for preclinical development • Use hepatocyte assays as indicators of low toxicity to refine panel of compounds • Initial clinical trials. License • Out license lead with initial preclinical & clinical data • License is a further Collaboration
  32. 32. Historic License Deals • University deal values are often not disclosed • May 2009 - Sanofi-Aventis will pay Exelixis up front fees of $141m for license rights to several cancer drugs – XL147 and XL765, both of which are in phase I trials – discovery of inhibitors of phosphoinositide-3 kinase for the treatment of cancer • May 2009 - Celgene will pay GlobeImmune $40m up front for an exclusive option – GlobeImmune's oncology programs, including GI-4000, currently in Phase II trials for pancreatic cancer
  33. 33. Advances in PGM Anticancer Agents • Excited-state Platinum • Organo-PGMs Ruthenium Osmium Iridium Opportunities for • Licensing patents • Collaboration in pre-clinical development Contacts: • Professor Peter Sadler, University of Warwick • Dr Shum Prakash, Business Development Manager Warwick Ventures, University House, Kirby Corner Road, Coventry CV4 8UW Tel: 024 7657 4145 E-mail: s.prakash@warwick.ac.uk
  34. 34. Acknowledgements • University of Warwick • ICT Biosciences, Bradford • University of Dundee/ • Czech Academy of Science Ninewells Hospital • Greifswald University • Warwick Ventures

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