1. Discovery of an Orally Bioavailable Small Molecule Inhibitor of Prosurvival B-Cell Lymphoma 2 Proteins.
- Author
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Cheol-Min Park, Milan Bruncko, Jessica Adickes, Joy Bauch, Hong Ding, Aaron Kunzer, Kennan C. Marsh, Paul Nimmer, Alexander R. Shoemaker, Xiaohong Song, Stephen K. Tahir, Christin Tse, Xilu Wang, Michael D. Wendt, Xiufen Yang, Haichao Zhang, Stephen W. Fesik, Saul H. Rosenberg, and Steven W. Elmore
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CHEMICAL inhibitors , *BIOAVAILABILITY , *MEMBRANE proteins , *CARCINOGENESIS , *CANCER treatment , *LABORATORY mice , *XENOGRAFTS , *PHARMACOKINETICS - Abstract
Overexpression of prosurvival proteins such as Bcl-2 and Bcl-X Lhas 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 1resulted 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 2is currently in multiple phase 1 clinical trials in patients with small cell lung cancer and hematological malignancies. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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