Journal article
ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets
AJ Souers, JD Leverson, ER Boghaert, SL Ackler, ND Catron, J Chen, BD Dayton, H Ding, SH Enschede, WJ Fairbrother, DCS Huang, SG Hymowitz, S Jin, SL Khaw, PJ Kovar, LT Lam, J Lee, HL Maecker, KC Marsh, KD Mason Show all
Nature Medicine | Published : 2013
DOI: 10.1038/nm.3048
Abstract
Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the latter is an established mechanism whereby cancer cells evade apoptosis. The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2-like 1 (BCL-X L), which has shown clinical efficacy in some BCL-2-dependent hematological cancers. However, concomitant on-target thrombocytopenia caused by BCL-X L inhibition limits the efficacy achievable with this agent. Here we report the re-engineering of navito..
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Funding Acknowledgements
We thank M. Bruncko, E. Fry, L. Hasvold, L. Hexamer, A. Kunzer, A. Petros, X. Song, Z. Tao, L. Wang and X. Wang for contributions to the generation of ABT-199 and related analogs and J. Bouska, and D. Osterling for analytical support. The authors acknowledge G. Chiang and A. Vasudevan for critical reading of this manuscript, L. Belmont, I. Wertz, J. Adams, S. Cory, P. Colman, P. Czabotar and G. Lessene for useful discussions and K. Lowes, E. Litvinovich and L. Roberts for technical analysis. Research performed at the Walter and Eliza Hall Institute (WEHI) was supported by grants and fellowships from the Australian National Health and Medical Research Council (NHMRC, including an Independent Research Institutes Infrastructure Support Scheme (IRIISS) grant), the Australian Cancer Research Foundation, the Leukaemia Foundation of Australia, the Cancer Council of Victoria, the Victorian Cancer Agency, the Victorian State Government Operational Infrastructure Support and the Leukemia Lymphoma Society. The authors acknowledge L.M. Staudt (US National Institutes of Health) for DLBCL cell lines.