Discovery of a Potent Inhibitor of the Antiapoptotic Protein Bcl-xL from NMR and Parallel
Synthesis

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.

doi:10.1021/jm0507532.s001

jm0507532_si_001.pdf (16.19 kB)

Discovery of a Potent Inhibitor of the Antiapoptotic Protein Bcl-x_L from NMR and Parallel Synthesis

journal contribution

posted on 2006-01-26, 00:00 authored by Andrew M. Petros, Jurgen Dinges, David J. Augeri, Steven A. Baumeister, David A. Betebenner, Mark G. Bures, Steven W. Elmore, Philip J. Hajduk, Mary K. Joseph, Shelley K. Landis, David G. Nettesheim, Saul H. Rosenberg, Wang Shen, Sheela Thomas, Xilu Wang, Irini Zanze, Haichao Zhang, Stephen W. Fesik

The antiapoptotic proteins Bcl-x_L 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-x_L and Bcl-2 attractive targets for the development of potential anticancer agents. Here we describe the structure-based discovery of a potent Bcl-x_L inhibitor directed at a hydrophobic groove on the surface of the protein. This groove represents the binding site for BH3 peptides from proapoptotic Bcl-2 family members such as Bak and Bad. Application of NMR-based screening yielded an initial biaryl acid with an affinity (K_d) of ∼300 μM for the protein. Following the classical “SAR by NMR” approach, a second-site ligand was identified that bound proximal to the first-site ligand in the hydrophobic groove. From NMR-based structural studies and parallel synthesis, a potent ligand was obtained, which binds to Bcl-x_L with an inhibition constant (K_i) of 36 ± 2 nM.