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  • Review Article
  • Published:

BCL-2 family antagonists for cancer therapy

Nature Reviews Drug Discovery volume 7, pages 989–1000 (2008)Cite this article

Key Points

  • The intrinsic pathway to apoptotic cell death converges on events at the mitochondrial outer membrane where interactions between the extended BCL-2 family of proteins determine the fate of the cell. The detailed mechanisms by which pro-survival and anti-survival factions of the family perform their roles remain under investigation.

  • There is now compelling evidence that cell death can be triggered by agents that mimic the action of a helical peptide in binding to the pro-survival family members. The target for these putative cytotoxic agents, an extended groove on the surface of the pro-survival BCL-2 family proteins, is a protein–protein interaction site, presenting particular challenges to drug discovery.

  • Cytotoxic activity does not necessarily require direct antagonism of the BCL-2 family, presenting challenges to establishing the mode of action.

  • More than a dozen candidate chemical classes have been claimed to antagonize one or more of the members of the pro-survival BCL-2 protein family. Most of these discoveries have come from screening compound libraries of one type or another. Design work has been limited to constrained helical peptides, terphenyls and benzoylureas, but only the helical peptides have interesting potency. Among the screening hits, many seem to exert their cytotoxicity through a non-apoptotic pathway.

  • Compounds that have progressed into clinical trials include GX15-070 (GeminX), AT-101 (Ascenta) and ABT-263 (Abbott). For only one of these three compound classes (ABT-263) is structural data currently available to guide further refinement of binding affinity and pharmacological properties.

  • GX15-070 (IC50 of the order of 1 μM for its BCL-2 targets) is effective as a single agent in killing multiple cancer cell lines in vitro and in vivo, and is administered intravenously in clinical trials against various haematological malignancies. This compound has also been shown to cause cell-cycle arrest, at concentrations lower than those that induce apoptosis. Further evaluation of its mechanism of action is needed.

  • AT-101 (IC50 of the order of 200 nM for its BCL-2 targets), the (–) enantiomer of gossypol, has similar in vitro cytotoxicity to GX15-070 and is administered orally in clinical studies for treatment of chronic lymphocytic leukaemia. Its mechanism of action is called into question by reports that gossypol kills cells lacking the apoptotic killers BAK and BAX.

  • ABT-263 (IC50 of the order of 1 nM for its BCL-2 targets), an orally available analogue of ABT-737, is insensitive to cells lacking BAK and BAX. It shows single-agent activity against various haematological tumours and small-cell lung carcinomas that have low levels of the pro-survival family member MCL1, to which ABT-263 shows no appreciable binding.

  • The mechanism of action of a bona fide BCL-2 family antagonist should be established by four criteria. One, cell-killing must be BAK/BAX dependent. Two, binding affinity for the relevant BCL-2 family targets should be in the low nanomolar range, similar to their physiological ligands. Three, the binding profile of the antagonist to the five pro-survival BCL-2 family members should correlate with cellular activity and expression levels of these proteins. Four, treatment of animals with the antagonist should trigger relevant biomarkers that correlate with the binding profile of the drug and the known biological roles of the five pro-survival family members.

Abstract

Overexpression of members of the BCL-2 family of pro-survival proteins is commonly associated with unfavourable pathogenesis in cancer. The convergence of cytotoxic stress signals on the extended BCL-2 protein family provides the biological rationale for directly targeting this family to induce apoptotic cell death. Recently, several compounds have been described that inhibit the interaction between BCL-2 family members and their natural ligand, a helical peptide sequence known as the BH3 domain. Here, we review preclinical and clinical data on these compounds, and recommend four criteria that define antagonists of the BCL-2 protein family.

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Figure 1: The extended BCL-2 protein family.
Figure 2: Structures of pro-survival proteins with BH3 ligands.
Figure 3: Interactions between proteins of the extended BCL-2 family determine the integrity of the outer mitochondrial membrane.
Figure 4: BH3 domain sequences of BH3-only proteins and their pro-survival protein binding targets.
Figure 5: Interactions between pro-survival BCL-2 proteins and BH3 ligands as exemplified by the MCL1–BIM BH3 complex.
Figure 6: Structural studies related to the discovery of ABT-737.

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Acknowledgements

We acknowledge helpful discussions with D. Huang and many other colleagues at The Walter and Eliza Hall Institute of Medical Research including J. Adams, J. Baell, S. Cory, D. Fairlie, E. Lee and K. Watson. Work in the authors' laboratories is supported by the National Health and Medical Research Council (Australia), The Leukemia and Lymphoma Society (USA), The Cancer Council of Victoria and The Australian Cancer Research Foundation.

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  1. The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, 3050, Victoria, Australia

    Guillaume Lessene, Peter E. Czabotar & Peter M. Colman

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Competing interests

The Walter and Eliza Hall Institute of Medical Research has an ongoing research collaboration agreement with Genentech and Abbott in the field of apoptosis, specifically BCL-2 family proteins.

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FURTHER INFORMATION

NCI's clinical trial results

Glossary

Mitochondrial pathway to programmed cell death

This pathway is activated by intracellular stresses and developmental cues. Also known as the intrinsic or stress pathway, it is regulated by the extended BCL-2 protein family. By contrast, the extrinsic apoptotic pathway is activated by cell-surface death receptors.

Caspase cascade

A proteolytic cascade that is initiated by both the mitochondrial pathway and the extrinsic pathway.

Autophagy

A cellular stress response in which non-vital cell components are broken down to provide nutrients for vital processes. Autophagy may also serve as an alternative non-apoptotic mechanism for cell death under certain conditions.

Lymphopaenia

A condition marked by lower than normal circulating lymphocytes.

Thrombocytopaenia

A decrease in platelet count, defined in humans as less than 150 million per ml, which results in the potential for increased bleeding.

Endoplasmic reticulum stress

Cellular disturbances causing an accumulation of unfolded proteins in the endoplasmic reticulum, which results in activation of the unfolded protein response.

Metathesis reaction

A transition metal-catalysed reaction used to manipulate alkenes.

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Lessene, G., Czabotar, P. & Colman, P. BCL-2 family antagonists for cancer therapy. Nat Rev Drug Discov 7, 989–1000 (2008). https://doi.org/10.1038/nrd2658

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