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 (indicated in red) or anti-apoptotic (green) consequences have a causative or contributing role in the pathogenesis or progression of several diseases. The clinical needs of most of these diseases have not yet been met. They include diseases that are characterized by inappropriate cell loss (stroke, heart failure, Alzheimers, Parkinsons) and illnesses that are associated with excessive cell accumulation (cancer) or failure to eradicate aberrant cells (autoimmunity). The emerging knowledge about proteins that are involved in apoptosis, including their biochemical mechanisms and threedimensional structures, has provided a foundation for drug discovery.

Sponsored by Merck Research Laboratories Boston

Therapeutic leads: pan-TRAILR: TRAIL TRAILR1: HGS-ETR1 TRAILR2: HGS-TR2J FAS: C75 | EGCG | Cerulenin

Death ligand (TNF, TRAIL, APO3L, FASL) Death receptor (TNFR1, TRAILR1, TRAILR2, APO3, FAS)

JNK pathway

Chemical lead: CDDO

FADD

Chemical leads: SPC-839 | SC-514 | Pyridooxazinone derivative | BMS-345541 | -carboline | 2-amino-6-[2-(cyclopropyl-methoxy)-6hydroxyphenyl]-4-piperidin-4-yl nicotinonitrile | Ureido-thiophene carboxamide derivative | Indole carboxamide derivative | Benzo-imidazole carboxamide derivative | Amino-imidazole carboxamide derivative | Pyridyl cyanoguanidine derivative | Anilino-pyrimidine derivative

Chemical lead*

Developing company or organization

Genta Inc. (Aventis) Raylight Chemokine Pharmaceuticals Inc. Harvard University University of Washington University of Michigan Yale University The Burnham Institute Harvard University Abbott Laboratories The Burnham Institute Serono Inc. The Blood Center of South Eastern Wisconsin The Burnham Institute Novartis Genome Foundation Abbott Laboratories University of Michigan The Burnham Institute University of Texas Southwestern Medical Center Aegera Therapeutics Inc. ISIS Pharmaceuticals Inc. (Lilly) University of Texas Southwestern Medical Center/ Abbott Laboratories IDUN Pharmaceuticals Inc. AstraZeneca Pharmaceuticals Merck & Co. Merck & Co. University of Illinois at Chicago Pfizer Inc. University Chemical Laboratory, UK Virginia Commonwealth University Schering-Plough Research Institute Hoffmann-La Roche Inc. Inotek Corp. Fujisawa Pharmaceutical Co., Ltd. Charing Cross Hospital University of Newcastle upon Tyne Harvard Medical School Guilford Pharmaceuticals Inc. Inotek Corp. National Cancer Institute Genentech Inc./Amgen Inc. Human Genome Sciences Inc./Kirin Johns Hopkins Medical Institutions University of Shizuoka Johns Hopkins Medical Institutions Signal Pharmaceuticals Inc. Pfizer Inc. Bayer AG Bristol-Myers Squibb Pharmaceutical Research Institute Millennium Pharmaceuticals Inc. Bayer Yakuhin Ltd. SmithKline Beecham Corp./AstraZeneca Aventis Pharma Aventis Pharma SmithKline Beecham Corp. LEO Pharma A/S Signal Pharmaceuticals Inc. Dartmouth College/Reata Discovery Inc. University of Arizona University of Bologna University of South Florida University of Fribourg, Switzerland Lilly Research Laboratories University of Arizona Tokyo Metropolitan Institute of Medical Science University of Tokyo Millennium Pharmaceuticals Inc. Yale University Molecular Medicine Research Institute/ The Burnham Institute National Institutes of Health/University of Texas M.D. Anderson Cancer Center Shanghai Second Medical University Universit Paris VII University of Arizona Memorial Sloan-Kettering Cancer Center Institut National de la Sant et de la Recherche Mdicale U-517, France

Target
BCL2 BCL2 BCL2 BCL2 BCL2 BCL2 BCL2 BCL2 BCL2 BAX BAX BAX BID IAP IAP

Stage

Refs

Growth factor

Growth factor receptor Chemical leads: DPIs | 1L-6-hydroxymethyl-chiroinositol 2(R)-2-O-methyl-3-Ooctadecylcarbonate | API-2 Chemical leads: Wortmannin | LY294002 | PX866

Withdrawal of growth factors/cytokines

JNK pathway

ASK1 TRAF2 IRE1 Endoplasmic reticulum (ER)

IKK

Chemical lead: 4-phenylsulphanylphenylamine derivatives Chemical leads: Benzenesulphonamide derivatives | Capped tripeptides containing unnatural amino acids | Embeline | Di/triphenylureas | Compound 3
BID

Chemical leads: Geldanamycin | PU24FCl HSP90 ? ?

PKC

PTEN

PI3K

Chemical leads: AQZs | Nicotinyl aspartyl ketones | M826 | M867

FLIP

AKT/ PKB P90RSK

Humanin DNA-PK (Ku70)

ER stress

Chemical leads: Humanin peptides | 3,6-dibromocarbazole piperazine derivatives of 2-propanol | Ku70 peptides
BCL-XL

BAX BAD

Chemical leads: HA14-1 analogues | CPM-1285 analogues | BH3I-1 | BH3I-2 | Antimycin A3 | Compound 6 | Terphenyl derivative | Apogossypol | Theaflavin | SAHBs | A-779024 BIM

Genasense HA14-1 analogues | CPM-1285 analogues BH3I-1 | BH3I-2 Antimycin A3 Compound 6 Terphenyl derivative Apogossypol | Theaflavin SAHBs A-779024 Humanin peptides 3,6-dibromocarbazole piperazine derivatives of 2-propanol Ku70 peptides 4-phenylsulphanyl-phenylamine derivatives Benzenesulphonamide derivatives Capped tripeptides containing unnatural amino acids Embeline Di/triphenylureas (1396-11,12,34) Compound 3 XIAP antisense (AEG35156/GEM640) Survivin antisense (ISIS 23722) -(trichloromethyl)-4-pyridineethanol (PETCM) IDN-6556 Anilinoquinazolines (AQZs) Nicotinyl aspartyl ketones M826 | M867 Pifithrin- CP-31398 Chlorofusin Sulphonamide compound 1 2-phenoxybenzoyl-tryptophan derivatives Nutlins INO-1001 FR255595 3-AB NU1025 | AG14361 INH2BP GPI6150 PJ34 Flavonoids TRAIL HGS-ETR1 | HGS-TR2J C75 Epigallocatechin gallate (EGCG) Cerulenin SPC-839 SC-514 Pyridooxazinone derivative BMS-345541 -carboline 2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-piperidin-4-yl nicotinonitrile Ureido-thiophene carboxamide derivative Indole carboxamide derivative Benzo-imidazole carboxamide derivative Amino-imidazole carboxamide derivative Pyridyl cyanoguanidine derivative Anilino-pyrimidine derivative 2-cyano-3,12-dioxoolean-1,9-bien-28-oic acid (CDDO) DPIs 1L-6-hydroxymethyl-chiro-inositol 2(R)2-O-methyl-3-O-octadecylcarbonate API-2 Wortmannin LY294002 PX866 MG-115, MG-132 Lactacystin Bortezomib (Velcade) Epoxomicin 3Cl-AHPC/MM11453 Gossypol/R-Gossypol Arsenicals Interferon Geldanamycin PU24FCl ADD70

(antisense)

Phase III 1,2 Preclinical 3,4 | 5 Preclinical 6 Preclinical 7 Preclinical 8 Preclinical 9 Preclinical 10,11 | 12 Preclinical 13 Preclinical Preclinical 14 Preclinical 15 Preclinical Preclinical Preclinical Preclinical Preclinical Preclinical Preclinical Phase I Phase I Preclinical Phase II Preclinical Preclinical Preclinical Preclinical Preclinical Preclinical Preclinical Preclinical Preclinical Phase I Phase I Preclinical Preclinical Preclinical Preclinical Preclinical Phase I Phase I Phase I Phase II Phase I Preclinical Preclinical Preclinical Preclinical Preclinical Preclinical Preclinical Preclinical Preclinical Preclinical Preclinical Preclinical Preclinical Preclinical Preclinical Preclinical Preclinical Preclinical Preclinical Preclinical Preclinical Preclinical Approved Preclinical Preclinical Phase II Phase I Phase I/II Phase II Preclinical Preclinical 16 17 18 19 20 21 22 23 24 25,26 27 28 29 | 30 31 32 33 34 35 36 37 38 39 40 | 41 42 43 44 45 46 47 | 48 49 5052 53 54 55 56 57 58 59 60 61 62 63 64 65 6668 69 70 71 72 73 74 75,76 77 78 7981 82 83,84 85 86 87 88 89

IAP IAP IAP XIAP Survivin APAF1? Pan-caspase Caspase-3 Caspase-3 Caspase-3 p53 p53 MDM2 MDM2 MDM2 MDM2 PARP PARP PARP PARP PARP PARP PARP CDKs || pan-TRAILR TRAILR1 | R2 FAS FAS FAS IKK IKK IKK IKK IKK IKK IKK IKK IKK IKK IKK IKK FLIP AKT/PKB AKT/PKB AKT/PKB PI3K PI3K PI3K 26S proteasome 26S proteasome 26S proteasome 26S proteasome NUR77/TR3 Topoisomerase II/ DNA polymerase|| PODs PODs HSP90 HSP90 HSP70

Caspase-12? ?

Caspase-8/10

? tBID
BAX

? VDAC PBR BCL2

BAK

Mitochondrion

SMAC/DIABLO

Chemical lead: Pan-caspase: IDN-6556

ANT
Caspase-3 IAP ARTS HTRA2/OMI

CYPD MPTP

Ca2+ release BI-1 BCL2 Caspase-7 Mitochondrion Ca2+ ? ICAD

XAF1 Cellular substrates IB Caspase-9 Cytochrome c

MMP
NFB BCL2

P53AIP1

BAGs
Apoptosome

NOXA

PUMA

APAF1 Chemical lead: ADD70

HSP70

EndoG

BIT1?

AIF

Calpains
CAD

Chemical leads: Pifithrin- | CP-31398

p53 Oncogenic signals p19ARF

Caspase-dependent cell death 26S proteasome

degradation

Therapeutic leads: Arsenicals | Interferon

Chemical leads: MG-115 | MG-132 | Lactacystin | Bortezomib | Epoxomicin

Caspase-independent cell death

Therapeutic lead: 3Cl-AHPC/MM11453 AIF

Nucleus

EndoG
DNA fragmentation

Chemical leads: INO-1001 | FR255595 | 3-AB | NU1025 | AG14361 | INH2BP | GPI6150 | PJ34

PML oncogenic domain (POD) PML ZIPK PAR4

Chemical lead: XIAP antisense

FLIP, cIAP2, BFL1, BCL-X

Chemical lead: Survivin antisense

Chemical lead: Genasense Survivin, BCL2

NUR77/TR3

DAXX NFB DNA damage

p53

p53

BAX, BAK, BID, NOXA, PUMA, APAF1, p53AIP1, FAS, TRAILR2, PIDD and other genes

DNA repair PARP CAD ATM

Chemical leads: Chlorofusin | Sulphonamide compound 1 | 2-phenoxybenzoyltryptophan derivatives | Nutlins

CHK2
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MDM2
Acknowledgements We acknowledge the help from D. Liu, A. Nie, J. Wang, J. An and M. Pellecchia in preparing this poster. Due to space constraints, only selected examples of chemical and therapeutic leads against apoptosis-relevant proteins are shown. John C. Reed and Ziwei Huang The Burnham Institute, 10901 N. Torrey Pines Rd, La Jolla, CA 92037, USA. e-mails: jreed@burnham.org; ziweihuang@burnham.org Designed by Simon Fenwick. Edited by Melanie Brazil and Arianne Heinrichs. Copyedited by Daniel Jones and Lesley Cunliffe. 2004 Nature Publishing Group. htpp://www.nature.com/reviews/poster/apoptosis

*Chemical leads against targets in the mitochondria-mediated pathway are listed, followed by the death-receptor pathway. Shown first are leads against the BCL2 family, as it is the prototypic apoptotic-protein family. For each target, the chemical leads are ordered according to either their stage of development (that is, compounds at clinical stage precede those at preclinical) or, when at the same stage, the time of their report in the literature. Pro-apoptotic and anti-apoptotic chemical leads are shown against a red and green background, respectively. It should be noted that some of the chemical leads interact with additional protein targets not listed here. Some targets such as the proteasome, NFB, HSP70 and HSP90 operate on many other proteins besides the apoptosis-relevant protein shown in the poster. Only antisense and 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.