926933-60-0Relevant articles and documents
Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-xL
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.
, p. 641 - 662 (2007/10/03)
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.
