nrm/nrd1104-poster.

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Apoptosis pathways and drug targets

John C. Reed and Ziwei Huang
Defects in the expression or function of proteins with either pro-apoptotic heart failure, Alzheimer’s, Parkinson’s) and illnesses that are associated
(indicated in red) or anti-apoptotic (green) consequences have a causative with excessive cell accumulation (cancer) or failure to eradicate aberrant
or contributing role in the pathogenesis or progression of several diseases. cells (autoimmunity). The emerging knowledge about proteins that are
The clinical needs of most of these diseases have not yet been met. They involved in apoptosis, including their biochemical mechanisms and three-
include diseases that are characterized by inappropriate cell loss (stroke, dimensional structures, has provided a foundation for drug discovery. Sponsored by Merck Research Laboratories – Boston

‡
Chemical lead* Developing company or organization Target Stage Refs
Death ligand Chemical leads: Growth factor Genasense (antisense)§ Genta Inc. (Aventis) BCL2 Phase III 1,2
(TNF, TRAIL, APO3L, FASL) SPC-839 | SC-514 | Pyridooxazinone
Therapeutic leads: HA14-1 analogues | CPM-1285 analogues Raylight Chemokine Pharmaceuticals Inc. BCL2 Preclinical 3,4 | 5
derivative | BMS-345541 | β-carboline |
pan-TRAILR: TRAIL BH3I-1 | BH3I-2 Harvard University BCL2 Preclinical 6
2-amino-6-[2-(cyclopropyl-methoxy)-6-
TRAILR1: HGS-ETR1 Death receptor Growth factor receptor Withdrawal of Antimycin A3 University of Washington BCL2 Preclinical 7
hydroxyphenyl]-4-piperidin-4-yl nicotinonitrile |
TRAILR2: HGS-TR2J (TNFR1, TRAILR1, growth factors/cytokines Compound 6 University of Michigan BCL2 Preclinical 8
Ureido-thiophene carboxamide derivative |
FAS: C75 | EGCG | Cerulenin TRAILR2, APO3, FAS) Terphenyl derivative Yale University BCL2 Preclinical 9
Indole carboxamide derivative | Chemical leads: Apogossypol | Theaflavin The Burnham Institute BCL2 Preclinical 10,11 | 12
Benzo-imidazole carboxamide derivative | DPIs | 1L-6-hydroxymethyl-chiro- SAHBs Harvard University BCL2 Preclinical 13
Amino-imidazole carboxamide derivative | inositol 2(R)-2-O-methyl-3-O- A-779024 Abbott Laboratories BCL2 Preclinical –
Pyridyl cyanoguanidine derivative | octadecylcarbonate | API-2 Humanin peptides The Burnham Institute BAX Preclinical 14
FADD Anilino-pyrimidine derivative 3,6-dibromocarbazole piperazine derivatives Serono Inc. BAX Preclinical 15
Chemical lead: of 2-propanol
JNK pathway CDDO Chemical leads: JNK pathway Ku70 peptides The Blood Center of South Eastern Wisconsin BAX Preclinical 16
Chemical lead: Chemical leads: PTEN Wortmannin | 4-phenylsulphanyl-phenylamine derivatives The Burnham Institute BID Preclinical 17
PKC PI3K LY294002 | PX866 Benzenesulphonamide derivatives Novartis Genome Foundation IAP Preclinical 18
IKK 4-phenylsulphanyl- Geldanamycin |
ASK1 phenylamine PU24FCl Capped tripeptides containing unnatural Abbott Laboratories IAP Preclinical 19
amino acids
derivatives
TRAF2 HSP90 Chemical leads: Embeline University of Michigan IAP Preclinical 20
Chemical leads: HA14-1 analogues | Di/triphenylureas (1396-11,12,34) The Burnham Institute IAP Preclinical 21
AQZs | Nicotinyl aspartyl FLIP Chemical leads: AKT/ Humanin DNA-PK Compound 3 University of Texas Southwestern Medical Center IAP Preclinical 22
IRE1α PKB (Ku70) CPM-1285 analogues |
ketones | M826 | M867 Benzenesulphonamide ? ? XIAP antisense (AEG35156/GEM640) § Aegera Therapeutics Inc. XIAP Phase I –
BH3I-1 | BH3I-2 |
derivatives | Capped P90RSK Antimycin A3 | Survivin antisense (ISIS 23722) § ISIS Pharmaceuticals Inc. (Lilly) Survivin Phase I 23
tripeptides containing Chemical leads: α-(trichloromethyl)-4-pyridineethanol (PETCM) University of Texas Southwestern Medical Center/ APAF1? Preclinical 24
Endoplasmic ? Compound 6 | Abbott Laboratories
reticulum (ER) unnatural amino acids | Humanin peptides | BAX Terphenyl derivative | IDN-6556 IDUN Pharmaceuticals Inc. Pan-caspase Phase II 25,26
ER stress Embeline | 3,6-dibromocarbazole Apogossypol | Anilinoquinazolines (AQZs) AstraZeneca Pharmaceuticals Caspase-3 Preclinical 27
Di/triphenylureas | piperazine derivatives BAD Theaflavin | SAHBs | Nicotinyl aspartyl ketones Merck & Co. Caspase-3 Preclinical 28
Compound 3 of 2-propanol | A-779024 M826 | M867 Merck & Co. Caspase-3 Preclinical 29 | 30
Ku70 peptides Pifithrin-α University of Illinois at Chicago p53 Preclinical 31
? ? BIM CP-31398 Pfizer Inc. p53 Preclinical 32
Caspase-12? Caspase-8/10 BID
BCL-XL tBID BAX BAK VDAC BCL2 Chlorofusin University Chemical Laboratory, UK MDM2 Preclinical 33
Mitochondrion Sulphonamide compound 1 Virginia Commonwealth University MDM2 Preclinical 34
? 2-phenoxybenzoyl-tryptophan derivatives Schering-Plough Research Institute MDM2 Preclinical 35
SMAC/DIABLO PBR Nutlins Hoffmann-La Roche Inc. MDM2 Preclinical 36
ANT INO-1001 Inotek Corp. PARP Phase I 37
Chemical lead: Caspase-3 IAP ARTS FR255595 Fujisawa Pharmaceutical Co., Ltd. PARP Phase I 38
Pan-caspase: IDN-6556 CYPD 3-AB Charing Cross Hospital PARP Preclinical 39
NU1025 | AG14361 University of Newcastle upon Tyne PARP Preclinical 40 | 41
HTRA2/OMI
MPTP INH2BP Harvard Medical School PARP Preclinical 42
XAF1 GPI6150 Guilford Pharmaceuticals Inc. PARP Preclinical 43
Ca2+ PJ34 Inotek Corp. PARP Preclinical 44
release Cellular Caspase-9 Cytochrome c Flavonoids National Cancer Institute CDKs || Phase I 45
substrates TRAIL § Genentech Inc./Amgen Inc. pan-TRAILR Phase I 46
MMP
BI-1 HGS-ETR1 § | HGS-TR2J § Human Genome Sciences Inc./Kirin TRAILR1 | R2 Phase I 47 | 48
BCL2 P53AIP1
C75 Johns Hopkins Medical Institutions FAS Phase II 49
IκB NFκB NOXA PUMA
BCL2 Caspase-7 BAGs Epigallocatechin gallate (EGCG) University of Shizuoka FAS Phase I 50–52
Cerulenin Johns Hopkins Medical Institutions FAS Preclinical 53
SPC-839 Signal Pharmaceuticals Inc. IKK Preclinical 54
Mitochondrion Apoptosome SC-514 Pfizer Inc. IKK Preclinical 55
ICAD APAF1 HSP70 EndoG BIT1? AIF Chemical leads: p53 Pyridooxazinone derivative Bayer AG IKK Preclinical 56
Ca2+ Oncogenic BMS-345541 Bristol-Myers Squibb Pharmaceutical Research Institute IKK Preclinical 57
Calpains Pifithrin-α |
CAD Chemical lead: CP-31398 signals β-carboline Millennium Pharmaceuticals Inc. IKK Preclinical 58
ADD70 ? ? 2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxy- Bayer Yakuhin Ltd. IKK Preclinical 59
? phenyl]-4-piperidin-4-yl nicotinonitrile
Caspase-dependent Caspase-independent p19ARF Ureido-thiophene carboxamide derivative SmithKline Beecham Corp./AstraZeneca IKK Preclinical 60
cell death 26S proteasome Chemical leads: cell death Indole carboxamide derivative Aventis Pharma IKK Preclinical 61

degradation Therapeutic lead: Benzo-imidazole carboxamide derivative Aventis Pharma IKK Preclinical 62
Therapeutic leads: MG-115 | MG-132 | 3Cl-AHPC/MM11453 Amino-imidazole carboxamide derivative SmithKline Beecham Corp. IKK Preclinical 63
Arsenicals | Interferon ? Lactacystin | Pyridyl cyanoguanidine derivative LEO Pharma A/S IKK Preclinical 64
Bortezomib | Epoxomicin Anilino-pyrimidine derivative Signal Pharmaceuticals Inc. IKK Preclinical 65
EndoG AIF Nucleus
2-cyano-3,12-dioxoolean-1,9-bien-28-oic Dartmouth College/Reata Discovery Inc. FLIP Preclinical 66–68
PML oncogenic DNA fragmentation acid (CDDO)
Chemical leads: domain (POD) DPIs University of Arizona AKT/PKB Preclinical 69
INO-1001 | FR255595 | Chemical lead: Chemical lead: Chemical lead: NUR77/TR3 1L-6-hydroxymethyl-chiro-inositol 2(R)- University of Bologna AKT/PKB Preclinical 70
2-O-methyl-3-O-octadecylcarbonate
3-AB | NU1025 | AG14361 | XIAP antisense Survivin antisense Genasense
PML PAR4 Chemical leads: API-2 University of South Florida AKT/PKB Preclinical 71
INH2BP | GPI6150 | PJ34
Chlorofusin | Wortmannin University of Fribourg, Switzerland PI3K Preclinical 72
ZIPK DAXX BAX, BAK, BID, NOXA, PUMA, Sulphonamide LY294002 Lilly Research Laboratories PI3K Preclinical 73
FLIP, cIAP2, Survivin, APAF1, p53AIP1, FAS, TRAILR2,
BFL1, BCL-X BCL2 compound 1 | PX866 University of Arizona PI3K Preclinical 74
PIDD and other genes 2-phenoxybenzoyl- MG-115, MG-132 Tokyo Metropolitan Institute of Medical Science 26S proteasome Preclinical 75,76
NFκB p53 p53
tryptophan derivatives | Lactacystin University of Tokyo 26S proteasome Preclinical 77
DNA damage
DNA Nutlins Bortezomib (Velcade) Millennium Pharmaceuticals Inc. 26S proteasome Approved 78
Epoxomicin Yale University 26S proteasome Preclinical 79–81
repair
3Cl-AHPC/MM11453 § Molecular Medicine Research Institute/ NUR77/TR3 Preclinical 82
The Burnham Institute
PARP CAD ATM
Gossypol/R-Gossypol National Institutes of Health/University of Texas Topoisomerase II/ Phase II 83,84
CHK2 p53 MDM2 M.D. Anderson Cancer Center DNA polymerase||
Arsenicals Shanghai Second Medical University PODs Phase I 85
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16. Sawada, M. et al. Nature Cell Biol. 5, 320–329 (2003). 32. Foster, B. A. et al. Science 286, 2507–2510 (1999). 47. Chuntharapai, A. et al. J. Immunol. 166, 4891–4898 (2001). 61. Tegeder, I. et al. J. Neurosci. 24, 1637–1645 (2004). 1195–1201 (1993). 89. Schmitt, E. et al. Cancer Res. 63, 8233–8240 (2003). htpp://www.nature.com/reviews/poster/apoptosis protein compounds that are in clinical development are listed and gene therapy is excluded. || CDKs and topoisomerase II/DNA polymerase are not indicated in the poster.