title: 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.affiliation: Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6101, USA.
authors.forename: Christin
authors.initials: C
authors.lastname: Tse
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Shoemaker
authors.forename: Jessica
authors.initials: J
authors.lastname: Adickes
authors.forename: Mark G
authors.initials: MG
authors.lastname: Anderson
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.forename: Sha
authors.initials: S
authors.lastname: Jin
authors.forename: Eric F
authors.initials: EF
authors.lastname: Johnson
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Mitten
authors.forename: Paul
authors.initials: P
authors.lastname: Nimmer
authors.forename: Lisa
authors.initials: L
authors.lastname: Roberts
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Tahir
authors.forename: Yu
authors.initials: Y
authors.lastname: Xiao
authors.forename: Xiufen
authors.initials: X
authors.lastname: Yang
authors.forename: Haichao
authors.initials: H
authors.lastname: Zhang
authors.forename: Stephen
authors.initials: S
authors.lastname: Fesik
authors.forename: Saul H
authors.initials: SH
authors.lastname: Rosenberg
authors.forename: Steven W
authors.initials: SW
authors.lastname: Elmore
mesh_terms: D000284:Administration, Oral; D000814:Aniline Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D018288:Carcinoma, Small Cell / Q000188:drug therapy / Q000473:pathology; D002478:Cells, Cultured; D004357:Drug Synergism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D000069283:Rituximab; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D000814:Aniline Compounds; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D000069283:Rituximab; C528561:navitoclax