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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
4
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pubmed:dateCreated |
2007-2-15
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pubmed:abstractText |
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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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Feb
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:BelliBarbara ABA,
pubmed-author:BrunckoMilanM,
pubmed-author:DingHongH,
pubmed-author:ElmoreSteven WSW,
pubmed-author:FesikStephen WSW,
pubmed-author:JosephMary KMK,
pubmed-author:KunzerAaronA,
pubmed-author:MartineauDarleneD,
pubmed-author:McClellanWilliam JWJ,
pubmed-author:MittenMichaelM,
pubmed-author:NgShi-ChungSC,
pubmed-author:NimmerPaul MPM,
pubmed-author:OltersdorfTilmanT,
pubmed-author:OostThorsten KTK,
pubmed-author:ParkCheol-MinCM,
pubmed-author:PetrosAndrew MAM,
pubmed-author:RosenbergSaul HSH,
pubmed-author:ShoemakerAlexander RAR,
pubmed-author:SongXiaohongX,
pubmed-author:WangXiluX,
pubmed-author:WendtMichael DMD,
pubmed-author:ZhangHaichaoH
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pubmed:issnType |
Print
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pubmed:day |
22
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pubmed:volume |
50
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
641-62
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pubmed:meshHeading |
pubmed-meshheading:17256834-Animals,
pubmed-meshheading:17256834-Antineoplastic Agents,
pubmed-meshheading:17256834-Biphenyl Compounds,
pubmed-meshheading:17256834-Cell Line, Tumor,
pubmed-meshheading:17256834-Drug Screening Assays, Antitumor,
pubmed-meshheading:17256834-Humans,
pubmed-meshheading:17256834-Lymphoma,
pubmed-meshheading:17256834-Mice,
pubmed-meshheading:17256834-Mice, SCID,
pubmed-meshheading:17256834-Models, Molecular,
pubmed-meshheading:17256834-Nitrophenols,
pubmed-meshheading:17256834-Piperazines,
pubmed-meshheading:17256834-Proto-Oncogene Proteins c-bcl-2,
pubmed-meshheading:17256834-Structure-Activity Relationship,
pubmed-meshheading:17256834-Sulfonamides,
pubmed-meshheading:17256834-Transplantation, Heterologous,
pubmed-meshheading:17256834-bcl-X Protein
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pubmed:year |
2007
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pubmed:articleTitle |
Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-xL.
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pubmed:affiliation |
Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA.
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pubmed:publicationType |
Journal Article
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