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

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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: s.prakash@warwick.ac.uk

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