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Objective Capital Precious Metals, Diamonds and Gemstones Investment Summit: Metals in Medicine - PGMs in anti-cancer treatments - Peter Sadler
- 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. Metals in Medicine - PGMs in anticancer treatments Peter J. Sadler FRS Professor of Chemistry University of Warwick
- 3. A Periodic Table of Medicines He B LiLiBe B C Ne NO F Mg Al Ar Ti Cr Fe S Cl Na Sc Ti V Cr Cu Ga Ge As2O Al N Br Kr 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 Sm Pr 201Tl Tm Ba Pt Au Bi 133Xe La
- 4. Design of metal compounds as therapeutic and diagnostic agents • There is enormous scope for design • Recent success with platinum shows that it is not just the metal which is important, but also the groups (ligands) which are bound to it • The shape of the complex (metal + ligands) is also important • I give examples here of novel anticancer PGM anticancer complexes which we have designed recently
- 5. Metals in Medicine- PGMs in anticancer treatments • Excited-state Platinum • Organo-PGMs - Ruthenium - Iridium - Osmium
- 6. Prof Peter Sadler’s Group > 30 years experience Track record of patents/commercial development includes • Pt radiosensitization agents • Gold anticancer compounds • Photactivated Pt anticancer agents • Organometallic Ru, Os and Ir anticancer agents
- 7. 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
- 8. Discovery of anticancer activity of cisplatin Barnett Rosenberg 1961 Professor of Biophysics Michigan State University + - Electric field lines Mitotic spindle for equal and opposite formation point charges during division of a eukaryotic cell Do electric fields affect cell division?
- 9. Effect of electric fields on cell growth “Inert” Pt electrodes Growth medium (NH4Cl) E. coli + cis-[PtCl2(NH3)2] Electrolysis led to small amounts of cisplatin Pt compounds in the medium- stops cell division Cisplatin approved by FDA 1978 1844 Peyrone's chloride
- 10. 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
- 11. Carboplatin Picoplatin FDA Approval Phase III trials 1989 Colorectal Metastatic Cancer Structure: Structure: S.Neidle, I.M. Ismail, P.J. Sadler Y. Chen, Z. Guo, J. Inorg. Biochem. S. Parsons, P.J. Sadler 1980 13 , 205-212. Chem. Eur. J. 1998, 4, 672-676. Work carried out in our laboratory on the structures of Pt anticancer drugs
- 12. Photochemotherapy Activation by light Directed therapy Destroys the cancer cells Less side-effects New approach to use of platinum in chemotherapy
- 13. Photochemotherapy Laser Cancer cell Drug Activation Active platinum species generated only in cancer cells- reduces side-effects on normal tissue
- 14. 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 Mackay, Woods, Heringová, Kaspárková, Pizarro, Moggach, Parsons, Brabec, Sadler PNAS 2007, 104, 20743-20748.
- 15. 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]
- 16. 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
- 17. Rh Prices of 2600 platinum Platinum group metals group metals Global Oxaliplatin Pt $48,000M $1,900M (2006) (2006) 1610 Carboplatin $673M (2004) Cisplatin Pd Ir $100M Platinum (1999) 483 Os 510 ca. 6% Ru 380 190 Cancer market Platinum sales Less expensive PMGs may also be US Dollars per troy useful as anticancer agents oz (31.1 g) [04/10]
- 18. Organo-PGMs ‘Piano-stool’ • Seat coated Complexes with carbon Ruthenium • Reactive Osmium Cisplatin leg(s) Iridium Different shape
- 19. 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
- 20. Tuning the reactivity of osmium complexes Reaction DNA Dose (hours) binding% (µM) 5 100 50 4 80 40 Os Cl O 3 60 30 R N Weak O Slow Inactive binding 2 40 20 1 20 10 No activity – Human ovarian now move the R group cancer cells van Rijt, Peacock, Johnstone, Parsons, Sadler, Inorg. Chem., 2009, 48 , 1753-62
- 21. Tuning the reactivity of osmium complexes Reaction DNA Dose (hours) binding% (µM) 5 100 50 Os 4 80 40 Cl O N 3 60 30 O Strong Fast Active binding 2 40 20 R 1 20 10 Activity of osmium controlled by the ligands- Human ovarian new design concepts cancer cells van Rijt, Peacock, Johnstone, Parsons, Sadler, Inorg. Chem., 2009, 48 , 1753-62
- 22. Anticancer Organo-PGMs Novel DNA interactions The organo coat can insert between DNA bases
- 23. Organo-osmium in ovarian cancer cell New target sites: new mechanism of action
- 24. Opportunities • Activity in human cancer cell lines can be comparable to or better than cisplatin • Different mechanisms of action : activity against cisplatin-resistant cells • Potentially less severe side-effects • Potential for combination therapy
- 25. Next Steps University • Structure-activity relationships • Mechanism of cancer cell cytotoxicity including cell uptake • Activity of lead compounds in well-established cancer models Collaboration Grants for • Establish a panel of lead compounds for preclinical development • Refine panel of compounds • Initial clinical trials. License • Out-license lead with initial preclinical & clinical data • License is a further collaboration
- 26. 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
- 27. Acknowledgements • University of Warwick • ICT Biosciences, Bradford • University of Dundee/ • Czech Academy of Science Ninewells Hospital • Greifswald University • Warwick Ventures
Editor's Notes
- Explain what Cytotoxic means Emphasize major and unmet! Mabs = monoclonal antibodies. Of the cytotoxics market? Here oxaliplatin 1b in 2006, next slide only 1.9M, At the moment the 5 year survival ates. So there is still a major unmet Medical
- Cisplatin the first chemotheraputic drugs discovered in the 1960’s is still in use in the clinic and had a sales in 1999 of 100M, second generation platinum drug carboplatin is most commonly used for ovarian and lung cancer , but may be used in the treatment of many other types, and third generation oxaliplatin also called elaxotin is commonly used to treat cancer of the large bowel . Despite of their succes , there are some drawbacks with these platinum drugs. Like nefrotoxicity, hair loss and nausea
- At warwick, we look at the rare metal osmium... The osmium compounds have a different shape as the platinum drug and more importantly the osmium compounds are organomettalic . Meaning that the osmium metal is surrounded by organic components, or organically coated if you like, shown here in yellow. These organic components allow for great scope of design. We have been studying these compound for years and we now have knowledge of how we can change their pharmacokinetics using these organic components.
- In summary, th elicense opportunity presented to you today is novel osmium compounds.. There is a hughe market oppurtonuity constituting 6 billion dollars and this is about 12% of the global cancer market. Combination therapy with pltinum drugs or other cancer therapies May wish to update this slide also.
- We are currently doing these things at the university We are collaborating to get to the stage a company will licence the technology which means we need to get initial in vivo and patient data to be able to license at the first yellow diamond on the earlier graph
- So the effort is high and the rewards are high…
- Peter sadler, 30 years of experience in developing drugs and was involved in the early work of carboplatin. With me today is shum prakash, wo is from our technology transfer office, warwick ventures. We have the same one here which is where we emphasised your track record before, but I think in your case, you could emphasise your track record at the beginning of the presentation.