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

Sb

Bi

Mn

Mo

Co

Si

SrSn

Ti

133Xe

201Tl

As90Y

188Re

153SmCs

La

SedoneuralBr

Cl

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

Metals in Medicine-PGMs in anticancer treatments

• Excited-state Platinum

• Organo-PGMs- Ruthenium- Iridium- Osmium

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

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

-+

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?

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

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

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

Activation by light

Photochemotherapy

Directed therapyDestroys the cancer cellsLess side-effects

New approach to use of platinum in chemotherapy

Drug Activation

Laser

Photochemotherapy

Cancercell

Active platinum species generated only in cancer cells-reduces side-effects on normal tissue

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.

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]

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

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

Organo-PGMs• Seat coated

with carbon

• Reactiveleg(s)

CisplatinDifferent shape

RutheniumOsmiumIridium

‘Piano-stool’Complexes

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

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

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

Anticancer Organo-PGMs

Novel DNA interactions

The organo coat can insert between DNA bases

Organo-osmium inovarian cancer cell

New target sites: new mechanism of action

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

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

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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: s.prakash@warwick.ac.uk

Opportunities for• Licensing patents

• Collaboration in pre-clinical development

• Organo-PGMsRutheniumOsmiumIridium

• Excited-statePlatinum

Acknowledgements

• University of Warwick• University of Dundee/

Ninewells Hospital• Warwick Ventures

• ICT Biosciences, Bradford• Czech Academy of Science• Greifswald University