2o2m

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[[Image:2o2m.gif|left|200px]]
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{{STRUCTURE_2o2m| PDB=2o2m | SCENE= }}
{{STRUCTURE_2o2m| PDB=2o2m | SCENE= }}
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'''Solution structure of the anti-apoptotic protein Bcl-xL in complex with an acyl-sulfonamide-based ligand'''
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===Solution structure of the anti-apoptotic protein Bcl-xL in complex with an acyl-sulfonamide-based ligand===
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==Overview==
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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.
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The line below this paragraph, {{ABSTRACT_PUBMED_17256834}}, adds the Publication Abstract to the page
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(as it appears on PubMed at http://www.pubmed.gov), where 17256834 is the PubMed ID number.
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{{ABSTRACT_PUBMED_17256834}}
==About this Structure==
==About this Structure==
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2O2M is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2O2M OCA].
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2O2M is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2O2M OCA].
==Reference==
==Reference==
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[[Category: Complex]]
[[Category: Complex]]
[[Category: Nmr]]
[[Category: Nmr]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 10:14:35 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Jul 27 18:50:58 2008''

Revision as of 15:51, 27 July 2008

Image:2o2m.png

Template:STRUCTURE 2o2m

Solution structure of the anti-apoptotic protein Bcl-xL in complex with an acyl-sulfonamide-based ligand

Template:ABSTRACT PUBMED 17256834

About this Structure

2O2M is a Single protein structure of sequence from Homo sapiens. Full experimental information is available from OCA.

Reference

Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-xL., Bruncko M, Oost TK, Belli BA, Ding H, Joseph MK, Kunzer A, Martineau D, McClellan WJ, Mitten M, Ng SC, Nimmer PM, Oltersdorf T, Park CM, Petros AM, Shoemaker AR, Song X, Wang X, Wendt MD, Zhang H, Fesik SW, Rosenberg SH, Elmore SW, J Med Chem. 2007 Feb 22;50(4):641-62. Epub 2007 Jan 26. PMID:17256834

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