2o21: Difference between revisions

[[Image:2o21.gif|left|200px]]<br /><applet load="2o21" size="350" color="white" frame="true" align="right" spinBox="true"  

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.

2O21 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=43B:'>43B</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2O21 OCA].  

[[Category: Belli, B A.]]

[[Category: Elmore, S W.]]

[[Category: Fesik, S W.]]

[[Category: Joseph, M K.]]

[[Category: McClellan, W J.]]

[[Category: Ng, S C.]]

[[Category: Nimmer, P M.]]

[[Category: Oost, T K.]]

[[Category: Park, C M.]]

[[Category: Petros, A M.]]

[[Category: Rosenberg, S H.]]

[[Category: Shoemaker, A R.]]

[[Category: Wendt, M D.]]

''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:13:32 2008''