Discovery of a potent inhibitor of the antiapoptotic protein Bcl-xL from NMR and parallel synthesis

…, J Dinges, DJ Augeri, SA Baumeister…

Index: Petros, Andrew M.; Dinges, Jurgen; Augeri, David J.; Baumeister, Steven A.; Betebenner, David A.; Bures, Mark G.; Elmore, Steven W.; Hajduk, Philip J.; Joseph, Mary K.; Landis, Shelley K.; Nettesheim, David G.; Rosenberg, Saul H.; Shen, Wang; Thomas, Sheela; Wang, Xilu; Zanze, Irini; Zhang, Haichao; Fesik, Stephen W. Journal of Medicinal Chemistry, 2006 , vol. 49, # 2 p. 656 - 663

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Citation Number: 248

Abstract

The antiapoptotic proteins Bcl-xL and Bcl-2 play key roles in the maintenance of normal cellular homeostasis. However, their overexpression can lead to oncogenic transformation and is responsible for drug resistance in certain types of cancer. This makes Bcl-xL and Bcl- 2 attractive targets for the development of potential anticancer agents. Here we describe the structure-based discovery of a potent Bcl-xL inhibitor directed at a hydrophobic groove on ...