BCL-2 family antagonists for cancer therapy View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2008-12

AUTHORS

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

ABSTRACT

Key PointsThe 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. More... »

PAGES

989-1000

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  • Journal

    TITLE

    Nature Reviews Drug Discovery

    ISSUE

    12

    VOLUME

    7

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nrd2658

    DOI

    http://dx.doi.org/10.1038/nrd2658

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1030857223

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/19043450


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