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
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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
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
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
Notas do Editor
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.