ABT-263: A Potent and Orally Bioavailable Bcl-2 Family Inhibitor

Tse, Christin; Shoemaker, Alexander R.; Adickes, Jessica; Anderson, Mark G.; Chen, Jun; Jin, Sha; Johnson, Eric F.; Marsh, Kennan C.; Mitten, Michael J.; Nimmer, Paul; Roberts, Lisa; Tahir, Stephen K.; Xiao, Yu; Yang, Xiufen; Zhang, Haichao; Fesik, Stephen; Rosenberg, Saul H.; Elmore, Steven W.

doi:10.1158/0008-5472.can-07-5836

Cited by 1,992Cell death mechanisms and regulationCancer-related Molecular PathwaysFlavonoids in Medical Research

ABT-263: A Potent and Orally Bioavailable Bcl-2 Family Inhibitor

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Tse, Christin, Shoemaker, Alexander R., Adickes, Jessica, Anderson, Mark G., Chen, Jun, Jin, Sha, Johnson, Eric F., Marsh, Kennan C. +10 more·2008·Cancer Research

DOI 10.1158/0008-5472.can-07-5836

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Abstract

Overexpression of the prosurvival Bcl-2 family members (Bcl-2, Bcl-xL, and Mcl-1) is commonly associated with tumor maintenance, progression, and chemoresistance. We previously reported the discovery of ABT-737, a potent, small-molecule Bcl-2 family protein inhibitor. A major limitation of ABT-737 is that it is not orally bioavailable, which would limit chronic single agent therapy and flexibility to dose in combination regimens. Here we report the biological properties of ABT-263, a potent, orally bioavailable Bad-like BH3 mimetic (K(i)'s of <1 nmol/L for Bcl-2, Bcl-xL, and Bcl-w). The oral bioavailability of ABT-263 in preclinical animal models is 20% to 50%, depending on formulation. ABT-263 disrupts Bcl-2/Bcl-xL interactions with pro-death proteins (e.g., Bim), leading to the initiation of apoptosis within 2 hours posttreatment. In human tumor cells, ABT-263 induces Bax translocation, cytochrome c release, and subsequent apoptosis. Oral administration of ABT-263 alone induces complete tumor regressions in xenograft models of small-cell lung cancer and acute lymphoblastic leukemia. In xenograft models of aggressive B-cell lymphoma and multiple myeloma where ABT-263 exhibits modest or no single agent activity, it significantly enhances the efficacy of clinically relevant therapeutic regimens. These data provide the rationale for clinical trials evaluating ABT-263 in small-cell lung cancer and B-cell malignancies. The oral efficacy of ABT-263 should provide dosing flexibility to maximize clinical utility both as a single agent and in combination regimens.

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ABT263 (navitoclax) is a Bcl-2 and Bcl-xl dual inhibitor.
“ABT263 (also known as navitoclax), a Bcl-2 and Bcl-xl dual inhibitor23,24, is one of the most potent and broad-spectrum senolytic agents identified to date16–18.”
From Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity (2020) · cites this paper as [23]

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Authors: Tse, C., Shoemaker, A. R., Adickes, J., Anderson, M. G., Chen, J., Jin, S., Johnson, E. F., Marsh, K. C., Mitten, M. J., Nimmer, P., Roberts, L., Tahir, S. K., Xiao, Y., Yang, X., Zhang, H., Fesik, S., Rosenberg, S. H., & Elmore, S. W.
Affiliations: Abbott (United States) (US)
Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois
ORCID: Anderson, Mark G.
Chen, Jun
Jin, Sha
Johnson, Eric F.
Marsh, Kennan C.
Nimmer, Paul
Tahir, Stephen K.
Zhang, Haichao
Fesik, Stephen
Venue: Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2008-05-01
Volume: 68
Issue: 9
Pages: 3421-3428
ISSN: 0008-5472 (ISSN-L)
1538-7445
DOI: 10.1158/0008-5472.can-07-5836
OpenAlex: W2168632005
Cited by: 1,992
References: 46
Citations by year: 2026: 72 · 2025: 93 · 2024: 117 · 2023: 131 · 2022: 114 · 2021: 141 · 2020: 154 · 2019: 113 · 2018: 96 · 2017: 105 · 2016: 113 · 2015: 141 · 2014: 123 · 2013: 121 · 2012: 98
FWCI: 36.57
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Cancer Research (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Health Sciences › Medicine › Pharmacology › Flavonoids in Medical Research
Keywords: navitoclax, ABT-737, BCL-2 inhibitor, BH3 mimetics, oral bioavailability, apoptosis, Bcl-2, Bcl-xL, Bcl-w, Bax translocation, cytochrome c release, small cell lung cancer, acute lymphoblastic leukemia, B-cell lymphoma, multiple myeloma, combination therapy, chemoresistance
MeSH terms: Rituximab, Administration, Oral, Aniline Compounds, Animals, Antibodies, Monoclonal, Antineoplastic Agents, Cells, Cultured, Drug Synergism, Humans, Lung Neoplasms, Models, Biological, Neoplasms, Sulfonamides, Thrombocytopenia, Mice, SCID, Treatment Outcome, Carcinoma, Small Cell, Mice, Knockout, Proto-Oncogene Proteins c-bcl-2, Lymphoma, Mantle-Cell, Xenograft Model Antitumor Assays, Tumor Burden, Mice, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Antibodies, Monoclonal, Murine-Derived

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ABT-263: A Potent and Orally Bioavailable Bcl-2 Family Inhibitor

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