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  • Review Article
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Promoting apoptosis as a strategy for cancer drug discovery

Nature Reviews Cancer volume 5, pages 876–885 (2005)Cite this article

A Corrigendum to this article was published on 01 December 2005

Key Points

  • In many cancers, the normal process for eliminating unwanted cells (apoptosis) is deregulated.

  • The deregulation of apoptosis leads to the unchecked growth of tumours and the development of resistance to chemotherapy.

  • Drugs that restore apoptosis might selectively kill cancer cells that have triggered a death signal and have become dependent on the deregulation of apoptosis pathways.

  • Agonistic antibodies against the tumour-necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptors and a soluble, truncated TRAIL ligand are in phase I/II clinical trials for the treatment of cancer.

  • BCL2 antisense oligonucleotides are in phase III clinical trials and pre-registration, and small-molecule BCL2-family inhibitors are in early phase I clinical trials and in late preclinical discovery for the treatment of chronic lymphocytic leukaemia and solid tumours.

  • IAP (inhibitor of apoptosis) protein inhibitors, MDM2 antagonists and other apoptosis-inducing compounds are under preclinical examination for possible use in cancer therapy.

  • For these compounds to succeed, it will be important to test them in well-designed clinical trials to determine the cancer patients that are most likely to respond to the particular agent, the optimum dose and schedule, and the best combination with other drugs.

Abstract

Apoptosis is deregulated in many cancers, making it difficult to kill tumours. Drugs that restore the normal apoptotic pathways have the potential for effectively treating cancers that depend on aberrations of the apoptotic pathway to stay alive. Apoptosis targets that are currently being explored for cancer drug discovery include the tumour-necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptors, the BCL2 family of anti-apoptotic proteins, inhibitor of apoptosis (IAP) proteins and MDM2.

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Figure 1: Simplified representation of the two main signalling pathways of programmed cell death.
Figure 2: Three-dimensional structures of BCL-XL and a two-dimensional structure of a BCL2-family inhibitor.
Figure 3: Anti-tumour activity of ABT-737 observed in vivo in a small cell lung carcinoma xenograft mouse model.
Figure 4: Structures of SMAC mimetics.
Figure 5: MDM2 inhibitors.

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Acknowledgements

The author wishes to thank A. Petros and E. Olejniczak for help in preparing the figures.

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  1. Department R460, Cancer Research, Abbott Laboratories, Building AP10-LL, 100 Abbott Park Road, Abbott Park, 60064, Illinois, USA

    Stephen W. Fesik

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DATABASES

Entrez Gene

APAF1

AKT

BAD

BAK

BAX

BCL2

BID

caspase 3

caspase 7

caspase 8

caspase 9

DR4

DR5

MDM2

p53

SMAC

survivin

TRAIL

XIAP

National Cancer Institute

leukaemias

melanoma

multiple myeloma

small cell lung carcinomas

Glossary

ANTIBODY-DEPENDENT CELLULAR CYTOTOXICITY

Immune cells interact with the Fc region of antibodies that are bound to a target cell through Fc receptors on their surface to mediate cell killing.

COMPLEMENT-DEPENDENT CYTOTOXICITY

Antibodies can kill target cells by binding the various components of complement. When combined, the components form pores in the cell membrane, which leads to phagocytosis or lysis.

ANTENNAPEDIA HOMEOPROTEIN

Cationic peptides derived from this protein can be attached to molecules to allow their transport into cells.

α, αDI-SUBSTITUTED UNNATURAL AMINO-ACIDS

Amino-acids with two additional chemical groups attached to the α-position.

TERPHENYL SCAFFOLD

A synthetic framework containing three phenyl rings that can be used to stabilize α-helical proteins and disrupt protein–protein interactions.

HETEROCYCLES

Ring compounds with both carbon atoms and atoms of other elements in the ring.

CHALCONE DERIVATIVES

1,3-diphenyl-2-propen-1-one analogues that are derived from ketones and are important intermediates in the synthesis of flavonoids. They are used to treat several diseases, including cancer.

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Fesik, S. Promoting apoptosis as a strategy for cancer drug discovery. Nat Rev Cancer 5, 876–885 (2005). https://doi.org/10.1038/nrc1736

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