1. Studies Leading to Potent, Dual Inhibitors of Bcl-2 and Bcl-xL.
- Author
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Milan Bruncko, Thorsten K. Oost, Barbara A. Belli, Hong Ding, Mary K. Joseph, Aaron Kunzer, Darlene Martineau, William J. McClellan, Michael Mitten, Shi-Chung Ng, Paul M. Nimmer, Tilman Oltersdorf, Cheol-Min Park, Andrew M. Petros, Alexander R. Shoemaker, Xiaohong Song, Xilu Wang, Michael D. Wendt, Haichao Zhang, and Stephen W. Fesik
- Subjects
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LYMPHOMAS , *CANCER cells , *CELL lines ,APOPTOSIS prevention - Abstract
Overexpression of the antiapototic proteins Bcl-2 and Bcl-xL provides a common mechanism through which cancer cells gain a survival advantage and become resistant to conventional chemotherapy. Inhibition of these prosurvival proteins is an attractive strategy for cancer therapy. We recently described the discovery of a selective Bcl-xL antagonist that potentiates the antitumor activity of chemotherapy and radiation. Here we describe the use of structure-guided design to exploit a deep hydrophobic binding pocket on the surface of these proteins to develop the first dual, subnanomolar inhibitors of Bcl-xL and Bcl-2. This study culminated in the identification of 2, which exhibited EC50values of 8 nM and 30 nM in Bcl-2 and Bcl-xL dependent cells, respectively. Compound 2demonstrated single agent efficacy against human follicular lymphoma cell lines that overexpress Bcl-2, and efficacy in a murine xenograft model of lymphoma when given both as a single agent and in combination with etoposide. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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