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Novel agents targeting the apoptosis pathway

Novel agents targeting the apoptosis pathway. Aaron D. Schimmer MD, PhD, FRCPC Princess Margaret Hospital Toronto, Canada. Cancer is an Elephant. Cancer is a defect In apoptosis. Therapy. Biology. Apoptosis. Survival. Survival. Survival. Survival. Death. Death. Death. Death.

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Novel agents targeting the apoptosis pathway

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  1. Novel agents targeting the apoptosis pathway Aaron D. Schimmer MD, PhD, FRCPCPrincess Margaret HospitalToronto, Canada

  2. Cancer is an Elephant Cancer is a defect In apoptosis

  3. Therapy Biology

  4. Apoptosis

  5. Survival Survival Survival Survival Death Death Death Death Receptors Receptors Receptors Receptors Receptors Receptors Receptors Receptors PTEN PTEN Fas Fas DR5 DR5 Flip Flip k k NF NF - - B B Reed JC, NDDR, 2002 Reed JC, NDDR, 2002 Ask1 Ask1 Ask1 Ask1 Cyt Cyt - - c c PI3K PI3K Apaf Apaf - - 1 1 Apaf Apaf - - 1 1 FADD FADD I I K K K K Casp Casp - - 8 8 Casp Casp Casp Casp - - - - 9 9 9 9 BAD BAD BAD BAD Akt Akt Akt Akt BAX BAX k k I I B B Bcl Bcl - - 2 2 IAPs IAPs IAPs IAPs Casp Casp Casp Casp - - - - 3 3 3 3 k k NF NF - - B B Nur77 Nur77 Bcl Bcl - - X X Casp Casp Casp Casp - - - - 6 6 6 6 Casp Casp Casp Casp - - - - 7 7 7 7 (TR3) (TR3) L L Bfl Bfl - - 1 1 FKHD FKHD FKHD FKHD Death Substrates Death Substrates Death Substrates Death Substrates ICAD/DFF; PARP; ICAD/DFF; PARP; Gelsolvin Gelsolvin , etc. , etc. ICAD/DFF; PARP; ICAD/DFF; PARP; Gelsolvin Gelsolvin , etc. , etc. PUMA PUMA NOXA NOXA p53 p53 Fas Fas - - L gene L gene Fas Fas - - L gene L gene

  6. Receptor Mediated Mitochondrial – (Extrinsic Pathway ) Mediated (Intrinsic Pathway) FAS / TRAIL Fadd / Mitochondria Mitochondria mort1 Cytochrome Cytochrome - - + C C Apaf - 1 Caspase - Caspase - Caspase - 8 9 3

  7. Receptor Mediated Mitochondrial – (Extrinsic Pathway ) Mediated (Intrinsic Pathway) FAS / TRAIL Fadd / Mitochondria Mitochondria mort1 FLIP Cytochrome Cytochrome - - + C C Apaf - 1 Caspase - Caspase - Caspase - 8 9 3 Granzyme B Granzyme B

  8. Receptor Mediated Mitochondrial – (Extrinsic Pathway ) Mediated (Intrinsic Pathway) FAS / TRAIL Fadd / Mitochondria Mitochondria mort1 Cytochrome Cytochrome - - + C C Apaf - 1 Caspase - Caspase - Caspase - 8 9 3 XIAP Granzyme B Granzyme B

  9. BIR 3 BIR 1 BIR 2 RING XIAP structure –function Casp –3/7 inhibition ? Ubiquitination Casp –9 inhibition

  10. Receptor Mediated Mitochondrial – (Extrinsic Pathway ) Mediated (Intrinsic Pathway) FAS / TRAIL Fadd / Bcl - 2 Mitochondria Mitochondria mort1 Cytochrome Cytochrome - - + C C Apaf - 1 Caspase - Caspase - Caspase - 8 9 3 Granzyme B Granzyme B

  11. Receptor Mediated Mitochondrial – (Extrinsic Pathway ) Mediated (Intrinsic Pathway) FAS / TRAIL Fadd / Bcl - 2 Mitochondria Mitochondria mort1 FLIP Cytochrome Cytochrome - - + C C Apaf - 1 Caspase - Caspase - Caspase - 8 9 3 XIAP Granzyme B Granzyme B

  12. Cyto-c Mitochondria Bcl-2: apoptosis and cell cycle M Bcl-2 G2 G1 S Bax

  13. Strategies to inhibit Bcl-2 Chemical Bcl-2 Inhibitors Antisense Oligonucleotides

  14. Bcl-2 Protein

  15. Bcl-2 Protein (with BH3 Peptide)

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