PRECIOUS METALS,DIAMONDS & GEMSTONES INVESTMENT SUMMIT
THE LONDON CHAMBER OF COMMERCE AND INDUSTRY ● THURSDAY, 20 MAY 2010www.ObjectiveCapitalConferences.com
2.40 – 3.05 Metals in Medicine - PGMs in anti-cancer treatmentsProf Peter Sadler – Professor of Chemistry, University of Warwick
Peter J. Sadler FRSProfessor of ChemistryUniversity of Warwick
Metals in Medicine -PGMs in anticancer treatments
He
Li Be B Ne
Al Ar
Sc Ti Cr Ga Ge As Br Kr
Rb Sr Y Zr Nb Ru Rh Pd Ag Cd In Sb Te Xe
Cs Ba La Hf Ta W Re Os Ir Pt Au Hg Tl Pb Bi
La Ce Pr Nd Sm Eu Gd Tb Dy Ho Er Tm Yb Lu
C
Pt Au
CrV
Ca Se
Li
99mTc
FeMg
Cu
Gd
I
F
Zn
Ag
Al
67Ga
B
N2O
NO
S
Ba
Na
K
A Periodic Tableof Medicines
P
SbBi
Mn
Mo
CoSi
SrSn
Ti
133Xe201Tl
As90Y
188Re153SmCs
La
SedoneuralBr
Cl
Metals in Medicine-PGMs in anticancer treatments
• Excited-state Platinum
• Organo-PGMs - Ruthenium- Iridium- Osmium
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 TechnologyFund/MMI/Oncosense - preclinical development)
• Organometallic Os and Ir anticancer (HEIF/EPSRC)
Prof Peter Sadler’s Group > 30 years experience
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
-+
Electric field linesfor equal and oppositepoint charges (electric dipole)
Mitotic spindle formationduring division ofa eukaryotic cell
Barnett Rosenberg1961 Professor of Biophysics Michigan State University
E. coli + cis- [PtCl2(NH3)2]cisplatin
Cisplatin approved by FDA 1978 1844 Peyrone's chloride
Effect of electric fields on cell growth
“Inert” Pt electrodes
Growth medium(NH4Cl)
1996 diagnosed with testicular cancerWon Tour de France each year from 1999 to 2005
Lance Armstrong
Platinum treatment
1979 diagnosed with testicular cancer1981 won theGrand National
Bob Champion MBE
Carboplatin
FDA Approval1989
PicoplatinPhase IIIColorectal Metastatic Cancer
Structure:S.Neidle, I.M. Ismail, P.J. Sadler J. Inorg. Biochem.1980 13 , 205-212.
Structure:Y. Chen, Z. Guo, S. Parsons, P.J. SadlerChem. Eur. J.1998, 4, 672-676.
Clinically Approved Platinum Anticancer Compounds
Cisplatin
ClPt
H3N
ClH3N
Oxaliplatin$1.9b 2006$3.4b 2012
Carboplatin$673m 2004
$100m 1999
Drawbacks• Acquired or inherent resistance• Toxic side effects
US Dollars per troy oz (31.1 g) [04/10]
Rh2600
Ru190
Pd483 Os
380
Ir510
Pt1610
Prices of platinum
group metals
Cancer market
Global$48,000M(2006)
Platinumca. 6%
Oxaliplatin$1,900M(2006)
Carboplatin$673M(2004)
Cisplatin$100M(1999)
Platinum sales
Platinum group metals
Activation by light
Photochemotherapy
Directed therapyDestroys the cancer cellsLess side-effects
Drug Activation
Laser
Photochemotherapy
Cancer cell
OH
Pt
OHN3H3N
NH3N3
OH
Pt
OH N
N3H3N
N3
>288
>244152
OH
Pt
OHN3H3N
N3H3NPt
ClH3N
ClH3N
>288Dark
Human Ovarian Cancer Cells
100
200
IC50μM
OH
Pt
OHN3H3N
NH3N3
OH
Pt
OH N
N3H3N
N3
133
99
>288
2
>244
151152
OH
Pt
OHN3H3N
N3H3NPt
ClH3N
ClH3N
>288Light Dark
100
200
IC50μM
Human Ovarian Cancer Cells
Potent photoactivatedplatinum anticancer
compound
Mackay, Woods, Heringová, Kaspárková, Pizarro, Moggach, Parsons, Brabec, Sadler PNAS 2007, 104, 20743-20748.
1 10 1000
50
100 DarkLight
µM
Cisplatin
Viable Cells (%)
Human bladder cancer cells
+100 µM Pt (dark)
Rapid rounding, “ballooning” of cells in light
50 µm
50 µm
+100 µM Pt (light)
[Bednarski, Grünert, Zielzki, Wellner, Mackay, Sadler, Chemistry & Biology, 2006, 13, 61-67]
25 µM 50 µM 100 µM
Cell shrinkage, loss of contact, nuclear packing and loss of nucleus
DAPI Fluorescence: stains duplex DNA
Human bladder cancer cells
Organo-PGMs• Seat coated
with carbon
• Reactive leg(s)
Cisplatin Different shape
Z
Y
RuX
R
Ru(II) Arene Anticancer Complexes
η6-arene
Leaving Group(s)
Yan, Melchart, Habtemariam, Sadler Chem. Commun. 2005, 4764 – 4776Dougan, Sadler Chimia , 2007, 61, 704-715
Z
Y
RuX
R
Ru(II) Arene Anticancer Complexes
η6-arene
Leaving Group(s)
Chelated Ligand
Tether
Yan, Melchart, Habtemariam, Sadler Chem. Commun. 2005, 4764 – 4776Dougan, Sadler Chimia , 2007, 61, 704-715
Tuning the activity of osmium compounds
10
20
30
40
50
Inactive
IC50(µM)
Human ovarian cancer cells
10
20
30
40
50
active
Human ovarian cancer cells
IC50(µM)
As active asCisplatin
Tuning the activity of osmium compounds
10
20
30
40
50
highly active
Human ovarian cancer cells
IC50(µM)
10x moreActive than Cisplatin
Tuning the activity of osmium compounds
I
10
20
30
40
50
Non-toxic
20
40
60
80
100
1
2
3
4
5
WeakbindingSlow
Human ovarian cancer cells
van Rijt, Peacock, Johnstone, Parsons, Sadler, Inorg. Chem., 2009, 48 , 1753-62
Dose(µM)
DNA binding%
Reaction (hours)
Tuning the reactivity of osmium complexes
Dose(µM)
10
20
30
40
50
Active
DNA binding%
20
40
60
80
100
Reaction (hours)
1
2
3
4
5
StrongbindingFast
Tuning the reactivity of osmium complexes
van Rijt, Peacock, Johnstone, Parsons, Sadler, Inorg. Chem., 2009, 48 , 1753-62
Human ovarian cancer cells
Anticancer Organo-PGMs
Novel DNA interactions
Organo-osmium inovarian 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 action : activity against cisplatin-resistant cells
• Potentially less severe side-effects• Easy synthesis, high yields and lower cost• Potential for combination therapy
Next Steps• Structure-activity relationships• Mechanism of cancer cell cytotoxicity including cell
uptake• Activity of lead compounds in well-established in vivo
cancer models• 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.• Out license lead with initial preclinical & clinical data• License is a further Collaboration
Uni
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olla
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tion
Lice
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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
Advances in PGM Anticancer Agents
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: [email protected]
Opportunities for• Licensing patents
• Collaboration in pre-clinical development
• Organo-PGMs RutheniumOsmiumIridium
• Excited-state Platinum
Acknowledgements
• University of Warwick• University of Dundee/
Ninewells Hospital• Warwick Ventures
• ICT Biosciences, Bradford• Czech Academy of Science• Greifswald University