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

Tse C, Shoemaker AR, Adickes J, Anderson MG, Chen J, Jin S, Johnson EF, Marsh KC, Mitten MJ, Nimmer P, Roberts L, Tahir SK, Xiao Y, Yang X, Zhang H, Fesik S, Rosenberg SH, Elmore SW
Cancer Res. 2008 68 (9): 3421-8

PMID: 18451170 · DOI:10.1158/0008-5472.CAN-07-5836

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.

MeSH Terms (25)

Administration, Oral Aniline Compounds Animals Antibodies, Monoclonal Antibodies, Monoclonal, Murine-Derived Antineoplastic Agents Carcinoma, Small Cell Cells, Cultured Drug Synergism Humans Lung Neoplasms Lymphoma, Mantle-Cell Mice Mice, Knockout Mice, SCID Models, Biological Neoplasms Precursor Cell Lymphoblastic Leukemia-Lymphoma Proto-Oncogene Proteins c-bcl-2 Rituximab Sulfonamides Thrombocytopenia Treatment Outcome Tumor Burden Xenograft Model Antitumor Assays

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