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Bcl-2 antagonists: a proof of concept for CLL therapy

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Summary

Defective apoptosis is a fundamental hallmark feature of CLL biology and is a major target of cancer therapy development. High levels of Bcl-2 family anti-apoptotic proteins are considered primarily responsible for inhibiting apoptosis in CLL cells. While several approaches were considered to selectively inhibit Bcl-2 family anti-apoptotic proteins, the discovery that gossypol binds and antagonizes anti-apoptotic effect of Bcl-2 family proteins was a major breakthrough in identifying specific Bcl-2 antagonists. The concept of mimicking BH3 domain emphasized the importance of Bcl-2 family-targeted therapy that can modulate the function of anti-apoptotic proteins. Although parent compound gossypol did not sustain in the clinic, its structural modifications led to the development of additional analogues that demonstrated improved efficacy and reduced toxicity in preclinical and clinical investigations. Proof of concept of this hypothesis was demonstrated by structure based BH3 mimetic ABT-737 that has shown greater cytotoxicity towards CLL cells both in pre-clinical models and clinical trials. Its oral compound ABT-263 has demonstrated the substantial susceptibility of chronic lymphocytic leukemia cells through Bcl-2 inhibition. Collectively, results of a Phase I Study of Navitoclax (ABT-263) in patients with relapsed or refractory disease warrants Bcl-2 as a valid therapeutic target in CLL. Importantly, molecules that mimic pro-apoptotic BH3 domains represent a direct approach to overcoming the protective effects of anti-apoptotic proteins such as Mcl-1, Bcl-2 and Bcl-XL.

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Acknowledgments

This work is supported in part by a CLL Consortium grant CA81534 from NCI and a CLL Global Research Foundation grant.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Kumudha Balakrishnan & Varsha Gandhi

  2. Department of Experimental Therapeutics, Unit 1950, The University of Texas M. D. Anderson Cancer Center, Houston, TX, 77230, USA

    Kumudha Balakrishnan & Varsha Gandhi

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  1. Kumudha Balakrishnan
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  2. Varsha Gandhi
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Correspondence to Kumudha Balakrishnan.

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Balakrishnan, K., Gandhi, V. Bcl-2 antagonists: a proof of concept for CLL therapy. Invest New Drugs 31, 1384–1394 (2013). https://doi.org/10.1007/s10637-013-0002-4

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  • DOI: https://doi.org/10.1007/s10637-013-0002-4

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