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 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
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. Metals in Medicine-
PGMs in anticancer treatments
• Excited-state Platinum
• Organo-PGMs
- Ruthenium
- Iridium
- Osmium

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. 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 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. 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. 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. 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. 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. 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. Photochemotherapy
Activation by light
Directed therapy
Destroys the cancer cells
Less side-effects

14. Photochemotherapy
Laser
Cancer
cell
Drug Activation

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. 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. 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. 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. 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. Organo-PGMs
• Seat coated
with carbon
• Reactive Cisplatin
leg(s) Different shape

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. 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. Tuning the activity
of osmium compounds IC50(µM)
50
40
30
Inactive
20
10
Human ovarian
cancer cells

24. Tuning the activity
of osmium compounds IC50(µM)
50
40
30
active
20
As active as
Cisplatin
10
Human ovarian
cancer cells

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. 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. 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. 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 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. 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-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. Acknowledgements
• University of Warwick • ICT Biosciences, Bradford
• University of Dundee/ • Czech Academy of Science
Ninewells Hospital • Greifswald University
• Warwick Ventures