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


  • 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 treatmentsPeter J. Sadler FRSProfessor of Chemistry University of Warwick 3. A Periodic Table of Medicines He B LiLiBeBC Ne NOFMg AlAr Ti Cr FeS ClSc TiCrCu Ga Ge As2O Br Kr AlNNa VMn Zn Si P Rb Sr Y Zr Nb Ru Rh Pd Ag Cd In Sb Te Xe KCo67Ga Ca Cs Ba La Hf Ta W Re Os Ir Pt Au Hg Tl Pb Bi Se90Y Mo 99mSn Br Sedoneural Sr TcAg AsI188Re Cs La Ce153 Nd Gd Sm Eu Gd Tb Dy Ho Er Sb Yb LuPrTm Sm 201TlBaPtAu Bi 133XeLa 4. Metals in Medicine- PGMs in anticancer treatments Excited-state Platinum Organo-PGMs- Ruthenium- Iridium- Osmium 5. Prof Peter Sadlers Group > 30 years experience Track record of patents/commercial development Pt radiosensitization agents (M&B/Rhne 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. 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. Barnett Rosenberg1961 Professor of BiophysicsMichigan State University + - Electric field linesMitotic spindle for equal and oppositeformation point charges during division of (electric dipole) a eukaryotic cell 8. Effect of electric fields on cell growthInert Pt electrodes Growth mediumE. coli + cis- [PtCl2(NH3)2] (NH4Cl) cisplatinCisplatin approved by FDA 19781844 Peyrone's chloride 9. Platinum treatmentBob Champion MBELance Armstrong1996 diagnosed with 1979 diagnosed withtesticular cancer testicular cancerWon Tour de France 1981 won the each year from Grand National 1999 to 2005 10. Carboplatin PicoplatinPhase IIIFDA ApprovalColorectal Metastatic1989Cancer Structure: Structure: S.Neidle, I.M. Ismail, Y. Chen, Z. Guo, P.J. SadlerS. Parsons, P.J. Sadler J. Inorg. Biochem. Chem. Eur. J. 1980 13 , 205-212. 1998, 4, 672-676. 11. Clinically Approved Platinum Anticancer Compounds H3N CarboplatinCl Pt$673m 2004 H3NCl Cisplatin$100m 1999Oxaliplatin$1.9b 2006 Drawbacks$3.4b 2012 Acquired or inherent resistance Toxic side effects 12. RhPrices of2600 platinum Platinum group metals group metalsPt Global Oxaliplatin1610 $48,000M $1,900M (2006) (2006) Carboplatin $673M (2004) PdIrCisplatin 483 Os 510$100M Platinum (1999)Ru380 ca. 6%190Cancer market Platinum sales US Dollars per troyoz (31.1 g) [04/10] 13. PhotochemotherapyActivation by light Directed therapy Destroys the cancer cells Less side-effects 14. Photochemotherapy LaserCancer cell Drug Activation 15. Human Ovarian Cancer CellsDark IC50 >288>288 M N3OH NH3 >244 200Pt 152H3NN3OH OH H3N N3PtH3NCl 100 OH N3 PtH3N N3 N OH H3NClPt H3N N3 OH 16. Human Ovarian Cancer CellsIC50Light Dark>288>288 M N3OH NH3>244 200Pt 152 133H3NOH N3 151OHH3NN399PtH3NCl 100 OHN3 PtH3N N3 NOHH3NClPt H3N OHN32 17. Potent photoactivatedplatinum anticancercompound 100 LightDark Viable Cells 50 (%) Cisplatin0110100 M Mackay, Woods, Heringov, Kasprkov, Pizarro, Moggach, Parsons, Brabec, Sadler PNAS 2007, 104, 20743-20748. 18. Human bladder cancer cells +100 M Pt (dark)+100 M Pt (light) 50 m50 m Rapid rounding, ballooning of cells in light [Bednarski, Grnert, Zielzki, Wellner, Mackay, Sadler, Chemistry & Biology, 2006, 13, 61-67] 19. Human bladder cancer cells 25 M50 M 100 M DAPI Fluorescence: stains duplex DNA Cell shrinkage, loss of contact,nuclear packing and loss of nucleus 20. Organo-PGMs Seat coatedwith carbon Reactive Cisplatin leg(s) Different shape 21. Ru(II) Arene Anticancer Complexes R 6-arene RuZ X LeavingY Group(s) Yan, Melchart, Habtemariam, Sadler Chem. Commun. 2005, 4764 4776 Dougan, Sadler Chimia , 2007, 61, 704-715 22. Ru(II) Arene Anticancer Complexes R 6-areneTetherRuZ XChelated LeavingY Ligand Group(s) Yan, Melchart, Habtemariam, Sadler Chem. Commun. 2005, 4764 4776 Dougan, Sadler Chimia , 2007, 61, 704-715 23. Tuning the activity of osmium compounds IC50(M) 5040 30Inactive2010Human ovariancancer cells 24. Tuning the activity of osmium compounds IC50(M) 504030active 20As active asCisplatin 10Human ovariancancer cells 25. Tuning the activity of osmium compounds IC50(M)50 40I 30 highly active20 10x more10 Active thanCisplatin Human ovariancancer cells 26. Tuning the reactivity of osmium complexesReaction DNA Dose (hours) binding%(M)5 100 50 4 8040 3 6030Weak Slow Non-toxic binding240 20 1 2010 Human ovarian cancer cellsvan Rijt, Peacock, Johnstone, Parsons, Sadler, Inorg. Chem., 2009, 48 , 1753-62 27. Tuning the reactivity of osmium complexesReaction DNA Dose (hours) binding%(M) 5100 504804036030 Strong FastActive binding 2402012010Human ovarian cancer cellsvan Rijt, Peacock, Johnstone, Parsons, Sadler, Inorg. Chem., 2009, 48 , 1753-62 28. Anticancer Organo-PGMs Novel DNA interactions 29. Organo-osmium in ovarian cancer cell New target sites: new mechanism of action 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. Next Steps Structure-activity relationshipsUniversity Mechanism of cancer cell cytotoxicity including cell uptake Activity of lead compounds in well-established in vivo cancer models CollaborationGrants 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. 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. Advances in PGM Anticancer Agents Excited-statePlatinum Organo-PGMsRutheniumOsmiumIridiumOpportunities 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. Acknowledgements University of Warwick ICT Biosciences, Bradford University of Dundee/ Czech Academy of Science Ninewells Hospital Greifswald University Warwick Ventures