Discovery of an Orally Bioavailable Small Molecule Inhibitor of Prosurvival B-Cell Lymphoma 2 Proteins

Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA.
Journal of Medicinal Chemistry (Impact Factor: 5.45). 11/2008; 51(21):6902-15. DOI: 10.1021/jm800669s
Source: PubMed


Overexpression of prosurvival proteins such as Bcl-2 and Bcl-X L has been correlated with tumorigenesis and resistance to chemotherapy, and thus, the development of antagonists of these proteins may provide a novel means for the treatment of cancer. We recently described the discovery of 1 (ABT-737), which binds Bcl-2, Bcl-X L, and Bcl-w with high affinity, shows robust antitumor activity in murine tumor xenograft models, but is not orally bioavailable. Herein, we report that targeted modifications at three key positions of 1 resulted in a 20-fold improvement in the pharmacokinetic/pharmacodynamic relationship (PK/PD) between oral exposure (AUC) and in vitro efficacy in human tumor cell lines (EC 50). The resulting compound, 2 (ABT-263), is orally efficacious in an established xenograft model of human small cell lung cancer, inducing complete tumor regressions in all animals. Compound 2 is currently in multiple phase 1 clinical trials in patients with small cell lung cancer and hematological malignancies.

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    • "Correspondence ª 2013 John Wiley & Sons Ltd proteins BCL2L1 and BCL2L2 (Oltersdorf et al, 2005; Park et al, 2008 "

    British Journal of Haematology 07/2013; 163(1). DOI:10.1111/bjh.12457 · 4.71 Impact Factor
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    • "Which patient groups might benefit from ABT-263? In addition to activity as monotherapy in animal models of lung cancer [12,49,114][11] and several lymphoid malignancies [11,12,15,62,85,115], ABT-737 or ABT-263 have also shown activity in combination with other drugs in animal models of numerous different cancer types. This includes the most prevalent cancers, breast [35,50], prostate [37], lung [92,116-118] and colorectal cancers [45] cancers. "
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    ABSTRACT: BH3 mimetics such as ABT-737 and navitoclax bind to the BCL-2 family of proteins and induce apoptosis through the intrinsic apoptosis pathway. There is considerable variability in the sensitivity of different cells to these drugs. Understanding the molecular basis of this variability will help to determine which patients will benefit from these drugs. Furthermore, this understanding aids in the design of rational strategies to increase the sensitivity of cells which are otherwise resistant to BH3 mimetics. We discuss how the expression of BCL-2 family proteins regulates the sensitivity to ABT-737. One of these, MCL-1, has been widely described as contributing to resistance to ABT-737 which might suggest a poor response in patients with cancers that express levels of MCL-1. In some cases, resistance to ABT-737 conferred by MCL-1 is overcome by the expression of pro-apoptotic proteins that bind to apoptosis inhibitors such as MCL-1. However, the distribution of the pro-apoptotic proteins amongst the various apoptosis inhibitors also influences sensitivity to ABT-737. Furthermore, the expression of both pro- and anti-apoptotic proteins can change dynamically in response to exposure to ABT-737. Thus, there is significant complexity associated with predicting response to ABT-737. This provides a paradigm for the multiplicity of intricate factors that determine drug sensitivity which must be considered for the full implementation of personalized medicine.
    Journal of Molecular Signaling 08/2012; 7(1):12. DOI:10.1186/1750-2187-7-12
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    • "This resistance to HDACI-mediated apoptosis was recently observed to be overcome by the combinational treatment of vorinostat and ABT-737 (the small molecule inhibitor of Bcl-2) in vitro and in vivo [125]. An ABT-737 homolog, ABT-263 has been developed and is orally bioavailable and is currently under investigation in clinical trials [126,127]. This data demonstrates the great potential for this rational combination strategy in human patients that may have developed refractory disease due to the up-regulation of anti-apoptotic Bcl-2 proteins (Figure 1). "
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    ABSTRACT: Advancement in the understanding of cancer development in recent years has identified epigenetic abnormalities as a common factor in both tumorigenesis and refractory disease. One such event is the dysregulation of histone deacetylases (HDACs) in both hematological and solid tumors, and has consequently resulted in the development of HDAC inhibitors (HDACI) to overcome this. HDACI exhibit pleiotropic biological effects including inhibition of angiogenesis and the induction of autophagy and apoptosis. Although HDACI exhibit modest results as single agents in preclinical and clinical data, they often fall short, and therefore HDACI are most promising in combinational strategies with either standard treatments or with other experimental chemotherapies and targeted therapies. This review will discuss the induction of autophagy and apoptosis and the inhibition of angiogenesis by HDACI, and also pre-clinical and clinical combination strategies using these agents.
    Pharmaceuticals 08/2010; 3(8). DOI:10.3390/ph3082441
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