Novel agents targeting the apoptosis pathway

Aaron D. Schimmer MD, PhD, FRCPCPrincess Margaret HospitalToronto, Canada

Cancer is an Elephant

Cancer is a defectIn apoptosis

Therapy Biology

Apoptosis

Ask1Ask1

FADD ApafApaf --11Casp -9Casp -9

Casp -3Casp -3

Casp -7Casp -7Casp -6Casp -6

BADBADCasp -8

AktAkt

Cyt-c

p53

Death SubstratesDeath SubstratesICAD/DFF; PARP; ICAD/DFF; PARP; GelsolvinGelsolvin , etc., etc.

IAPsIAPs

BAXBcl -2

Bcl -XLBfl-1

PUMA NOXA

NF-kB

IkB

IKK

PI3K

FasFas --L geneL gene

FKHDFKHD

Nur77(TR3)

FasDR5

NF-kB

FlipPTEN

DeathDeathReceptorsReceptors

SurvivalSurvivalReceptorsReceptors

Reed JC, NDDR, 2002

Ask1Ask1

FADD ApafApaf --11Casp -9Casp -9

Casp -3Casp -3

Casp -7Casp -7Casp -6Casp -6

BADBADCasp -8

AktAkt

Cyt -c

p53

Death SubstratesDeath SubstratesICAD/DFF; PARP; ICAD/DFF; PARP; GelsolvinGelsolvin , etc., etc.

IAPsIAPs

BAXBcl -2

Bcl -XLBfl -1

PUMA NOXA

NF-B

IB

IKK

PI3K

FasFas -- L geneL gene

FKHDFKHD

Nur77(TR3)

FasDR5

NF-B

FlipPTEN

DeathDeathReceptorsReceptors

SurvivalSurvivalReceptorsReceptors

Reed JC, NDDR, 2002

MitochondriaMitochondria

CytochromeCytochrome--CC

Caspase-9Caspase-

3

Caspase-8

Fadd/ mort1

FAS/TRAIL

+Apaf-

1

Mitochondrial –Mediated (Intrinsic Pathway)

Receptor Mediated (Extrinsic Pathway)

MitochondriaMitochondria

CytochromeCytochrome--CC

Caspase-9Caspase-

3

Caspase-8

Fadd/ mort1

FAS/TRAIL

Granzyme BGranzyme B

+Apaf-

1

Mitochondrial –Mediated (Intrinsic Pathway)

Receptor Mediated (Extrinsic Pathway)

FLIP

MitochondriaMitochondria

CytochromeCytochrome--CC

Caspase-9Caspase-

3

Caspase-8

Fadd/ mort1

FAS/TRAIL

Granzyme BGranzyme B

+Apaf-

1

Mitochondrial –Mediated (Intrinsic Pathway)

Receptor Mediated (Extrinsic Pathway)

XIAP

? Casp –3/7inhibition

Ubiquitination

BIR 1BIR 1 RING BIR 2BIR 2 BIR 3BIR 3

Casp –9inhibition

XIAP structure –functionXIAP structure –function

MitochondriaMitochondria

CytochromeCytochrome--CC

Caspase-9Caspase-

3

Caspase-8

Fadd/ mort1

FAS/TRAIL

Granzyme BGranzyme B

+Apaf-

1

Mitochondrial –Mediated (Intrinsic Pathway)

Receptor Mediated (Extrinsic Pathway)

Bcl-2

MitochondriaMitochondria

CytochromeCytochrome--CC

Caspase-9Caspase-

3

Caspase-8

Fadd/ mort1

FAS/TRAIL

Granzyme BGranzyme B

+Apaf-

1

Mitochondrial –Mediated (Intrinsic Pathway)

Receptor Mediated (Extrinsic Pathway)

XIAP

FLIP

Bcl-2

•

Bcl-2: apoptosis and cell Bcl-2: apoptosis and cell cyclecycle

MitochondriaMitochondria

Cyto-cCyto-c

Bcl-2Bcl-2

Bax

M

S

G1 G2

Strategies to inhibit Bcl-2

Antisense Oligonucleotides

ChemicalBcl-2 Inhibitors

Bcl-2 ProteinBcl-2 Protein

Bcl-2 ProteinBcl-2 Protein(with BH3 Peptide)(with BH3 Peptide)