Details

Autor(en) / Beteiligte

• Bruncko, Milan
• Oost, Thorsten K
• Belli, Barbara A
• Ding, Hong
• Joseph, Mary K
• Kunzer, Aaron
• Martineau, Darlene
• McClellan, William J
• Mitten, Michael
• Ng, Shi-Chung
• Nimmer, Paul M
• Oltersdorf, Tilman
• Park, Cheol-Min
• Petros, Andrew M
• Shoemaker, Alexander R
• Song, Xiaohong
• Wang, Xilu
• Wendt, Michael D
• Zhang, Haichao
• Fesik, Stephen W
• Rosenberg, Saul H
• Elmore, Steven W

Titel

Studies Leading to Potent, Dual Inhibitors of Bcl-2 and Bcl-xL

Ist Teil von

• Journal of medicinal chemistry, 2007-02, Vol.50 (4), p.641-662

Ort / Verlag

Washington, DC: American Chemical Society

Erscheinungsjahr

2007

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 EC50 values of 8 nM and 30 nM in Bcl-2 and Bcl-xL dependent cells, respectively. Compound 2 demonstrated 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.