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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
24
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pubmed:dateCreated |
2009-12-17
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pubmed:abstractText |
Dramatic improvements in mTOR-targeting selectivity were achieved by replacing morpholine in pyrazolopyrimidine inhibitors with bridged morpholines. Analogues with subnanomolar mTOR IC(50) values and up to 26000-fold selectivity versus PI3Kalpha were prepared. Chiral morpholines gave inhibitors whose enantiomers had different selectivity and potency profiles. Molecular modeling suggests that a single amino acid difference between PI3K and mTOR (Phe961Leu) accounts for the profound selectivity seen by creating a deeper pocket in mTOR that can accommodate bridged morpholines.
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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 |
Dec
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pubmed:issn |
1520-4804
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pubmed:author |
pubmed-author:Ayral-KaloustianSemiramisS,
pubmed-author:BennettEric MEM,
pubmed-author:BrooijmansNatasjaN,
pubmed-author:CurranKevinK,
pubmed-author:HollanderIrwinI,
pubmed-author:KaplanJoshuaJ,
pubmed-author:MayAA,
pubmed-author:RichardDavid JDJ,
pubmed-author:Toral-BarzaLourdesL,
pubmed-author:VerheijenJeroen CJC,
pubmed-author:ZaskArieA
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pubmed:issnType |
Electronic
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pubmed:day |
24
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pubmed:volume |
52
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
7942-5
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pubmed:dateRevised |
2010-11-18
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pubmed:meshHeading |
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pubmed:year |
2009
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pubmed:articleTitle |
Morpholine derivatives greatly enhance the selectivity of mammalian target of rapamycin (mTOR) inhibitors.
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pubmed:affiliation |
Chemical Sciences, Wyeth Research, Pearl River, NY 10965, USA. zaska@wyeth.com
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pubmed:publicationType |
Journal Article
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