ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor.

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.

• Authors: Christin Tse, Alexander R Shoemaker, Jessica Adickes, Mark G Anderson, Jun Chen, Sha Jin, Eric F Johnson, Kennan C Marsh, Michael J Mitten, Paul Nimmer, Lisa Roberts, Stephen K Tahir, Yu Xiao, Xiufen Yang, Haichao Zhang, Stephen Fesik, Saul H Rosenberg, Steven W Elmore
• Journal: Cancer research (Cancer Res) Vol. 68 Issue 9 Pg. 3421-8 (May 01 2008) ISSN: 1538-7445 [Electronic] United States
• PMID: 18451170 (Publication Type: Journal Article)

Chemical References

• Aniline Compounds
• Antibodies, Monoclonal
• Antibodies, Monoclonal, Murine-Derived
• Antineoplastic Agents
• Proto-Oncogene Proteins c-bcl-2
• Sulfonamides
• Rituximab
• navitoclax

Topics

• Administration, Oral
• Aniline Compounds (administration & dosage, adverse effects, therapeutic use)
• Animals
• Antibodies, Monoclonal (administration & dosage)
• Antibodies, Monoclonal, Murine-Derived
• Antineoplastic Agents (administration & dosage, adverse effects, therapeutic use)
• Carcinoma, Small Cell (drug therapy, pathology)
• Cells, Cultured
• Drug Synergism
• Humans
• Lung Neoplasms (drug therapy, pathology)
• Lymphoma, Mantle-Cell (drug therapy, pathology)
• Mice
• Mice, Knockout
• Mice, SCID
• Models, Biological
• Neoplasms (drug therapy, pathology)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (complications, drug therapy, pathology)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors)
• Rituximab
• Sulfonamides (administration & dosage, adverse effects, therapeutic use)
• Thrombocytopenia (chemically induced)
• Treatment Outcome
• Tumor Burden
• Xenograft Model Antitumor Assays