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![Page 1: Objective Capital Precious Metals, Diamonds and Gemstones Investment Summit: Metals in Medicine - PGMs in anti-cancer treatments - Peter Sadler](https://reader033.fdocuments.us/reader033/viewer/2022051413/558679e3d8b42a395a8b457a/html5/thumbnails/1.jpg)
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
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Peter J. Sadler FRSProfessor of ChemistryUniversity of Warwick
Metals in Medicine -PGMs in anticancer treatments
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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
Sb
Bi
Mn
Mo
Co
Si
SrSn
Ti
133Xe
201Tl
As90Y
188Re
153SmCs
La
SedoneuralBr
Cl
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Design of metal compounds astherapeutic and diagnostic agents
• There is enormous scope for design
• Recent success with platinum shows that it isnot just the metal which is important, but alsothe groups (ligands) which are bound to it
• The shape of the complex (metal + ligands) isalso important
• I give examples here of novel anticancer PGManticancer complexes which we have designedrecently
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Metals in Medicine-PGMs in anticancer treatments
• Excited-state Platinum
• Organo-PGMs- Ruthenium- Iridium- Osmium
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Track record of patents/commercial developmentincludes
• Pt radiosensitization agents
• Gold anticancer compounds
• Photactivated Pt anticancer agents
• Organometallic Ru, Os and Ir anticancer agents
Prof Peter Sadler’s Group > 30 years experience
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Major Unmet Medical Need• Cytotoxics (drugs that kill cells) market
segment that includes platinum-basedtherapeutics 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
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-+
Electric field linesfor equal and oppositepoint charges
Mitotic spindleformationduring division ofa eukaryotic cell
Discovery of anticancer activityof cisplatinBarnett Rosenberg1961 Professor of BiophysicsMichigan State University
Do electric fields affect cell division?
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E. coli + cis-[PtCl2(NH3)2]cisplatin
Cisplatinapprovedby FDA1978
1844 Peyrone's chloride
Effect of electric fields on cell growth
“Inert” Ptelectrodes
Growth medium(NH4Cl)
Electrolysis led to small amounts ofPt compounds in the medium- stops cell division
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Clinically Approved PlatinumAnticancer 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
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CarboplatinFDA Approval1989
PicoplatinPhase III trialsColorectal MetastaticCancer
Structure:S.Neidle, I.M. Ismail, P.J. SadlerJ. Inorg. Biochem.1980 13 , 205-212.
Structure:Y. Chen, Z. Guo,S. Parsons, P.J. SadlerChem. Eur. J. 1998, 4, 672-676.
Work carried out in our laboratory on the structures of Pt anticancer drugs
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Activation by light
Photochemotherapy
Directed therapyDestroys the cancer cellsLess side-effects
New approach to use of platinum in chemotherapy
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Drug Activation
Laser
Photochemotherapy
Cancercell
Active platinum species generated only in cancer cells-reduces side-effects on normal tissue
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OH
Pt
OHN3H3N
NH3N3
OH
Pt
OH N
N3H3N
N3
133
99
>288
2
>244
151
152
OH
Pt
OHN3H3N
N3H3NPt
ClH3N
ClH3N
>288Light Dark
100
200
IC50
μM
Human Ovarian Cancer Cells
Mackay, Woods, Heringová, Kaspárková, Pizarro, Moggach, Parsons, Brabec, Sadler PNAS 2007, 104, 20743-20748.
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Human bladder cancer cellsHuman 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]
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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 cellsHuman bladder cancer cells
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US Dollars per troyoz (31.1 g) [04/10]
Rh2600
Ru190
Pd483 Os
380
Ir510
Pt1610
Prices ofplatinum
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
Less expensive PMGs may also beuseful as anticancer agents
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Organo-PGMs• Seat coated
with carbon
• Reactiveleg(s)
CisplatinDifferent shape
RutheniumOsmiumIridium
‘Piano-stool’Complexes
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Z
Y
RuX
R
Ru(II) Arene Anticancer Complexes
η6-arene
LeavingGroup(s)
ChelatedLigand
Tether
Yan, Melchart, Habtemariam, Sadler Chem. Commun. 2005, 4764 – 4776Dougan, Sadler Chimia , 2007, 61, 704-715
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10
20
30
40
50
Inactive
20
40
60
80
100
1
2
3
4
5
WeakbindingSlow
Human ovariancancer cells
Os
Cl O
ONR
van Rijt, Peacock, Johnstone, Parsons, Sadler, Inorg. Chem., 2009, 48 , 1753-62
Dose(µM)
DNAbinding%
Reaction(hours)
Tuning the reactivity of osmium complexes
No activity –now move the R group
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Dose(µM)
10
20
30
40
50
Active
DNAbinding%
20
40
60
80
100
Reaction(hours)
1
2
3
4
5
StrongbindingFast
Tuning the reactivity of osmium complexes
Os
ClN
O
O
R
van Rijt, Peacock, Johnstone, Parsons, Sadler, Inorg. Chem., 2009, 48 , 1753-62
Human ovariancancer cells
Activity of osmium controlledby the ligands-
new design concepts
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Anticancer Organo-PGMs
Novel DNA interactions
The organo coat can insert between DNA bases
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Organo-osmium inovarian cancer cell
New target sites: new mechanism of action
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Opportunities
• Activity in human cancer cell lines can becomparable to or better than cisplatin
• Different mechanisms of action :activity against cisplatin-resistant cells
• Potentially less severe side-effects• Potential for combination therapy
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Next Steps• Structure-activity relationships• Mechanism of cancer cell cytotoxicity including cell
uptake• Activity of lead compounds in well-established
cancer models• Establish a panel of lead compounds for preclinical
development• Refine panel of compounds• Initial clinical trials.• Out-license lead with initial preclinical & clinical data• License is a further collaboration
Uni
vers
ityG
rant
sfo
rC
olla
bora
tion
Lice
nse
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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 8UWTel: 024 7657 4145 E-mail: [email protected]
Opportunities for• Licensing patents
• Collaboration in pre-clinical development
• Organo-PGMsRutheniumOsmiumIridium
• Excited-statePlatinum
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Acknowledgements
• University of Warwick• University of Dundee/
Ninewells Hospital• Warwick Ventures
• ICT Biosciences, Bradford• Czech Academy of Science• Greifswald University