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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
8
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pubmed:dateCreated |
2010-4-15
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pubmed:abstractText |
Significant evidence suggests that deregulation of the PI3K/Akt pathway is important in tumor progression. Mechanisms include loss of function of the tumor suppressor PTEN and high frequency of mutation of the PI3K p110alpha isoform in human malignancies. This connection between PI3K and tumor genesis makes PI3K a promising target for cancer treatment. A series of 4-morpholinopyrrolopyrimidine derivatives were synthesized and evaluated as inhibitors of PI3Kalpha and mTOR, leading to the discovery of PI3Kalpha selective inhibitors (e.g., 9) and dual PI3Kalpha/mTOR kinase inhibitors (e.g., 46 and 48). PI3Kalpha/mTOR dual inhibitors demonstrated inhibition of tumor cell growth in vitro and in vivo and caused suppression of the pathway specific biomarkers [e.g., the phosphorylation of Akt at Thr308 (T308) and Ser473 (S473)] in the human breast cancer cell line MDA361. In addition, compound 46 demonstrated good in vivo efficacy in the MDA361 human breast tumor xenograft model.
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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 |
http://linkedlifedata.com/resource/pubmed/chemical/Benzamides,
http://linkedlifedata.com/resource/pubmed/chemical/Intracellular Signaling Peptides...,
http://linkedlifedata.com/resource/pubmed/chemical/MTOR protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Morpholines,
http://linkedlifedata.com/resource/pubmed/chemical/Phenylurea Compounds,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphatidylinositol 3-Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Protein-Serine-Threonine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-akt,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrimidines,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrroles,
http://linkedlifedata.com/resource/pubmed/chemical/TOR Serine-Threonine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/mTOR protein, mouse
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pubmed:status |
MEDLINE
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pubmed:month |
Apr
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pubmed:issn |
1520-4804
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pubmed:author |
pubmed-author:Ayral-KaloustianSemiramisS,
pubmed-author:BrooijmansNatasjaN,
pubmed-author:ChenZechengZ,
pubmed-author:DehnhardtChristoph MCM,
pubmed-author:FeldbergLarryL,
pubmed-author:HollanderIrwinI,
pubmed-author:KongFangmingF,
pubmed-author:LucasJudyJ,
pubmed-author:MallonRobertR,
pubmed-author:MansourTarek STS,
pubmed-author:MayAA,
pubmed-author:VenkatesanAranapakam MAM
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pubmed:issnType |
Electronic
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pubmed:day |
22
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pubmed:volume |
53
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
3169-82
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pubmed:dateRevised |
2010-11-18
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pubmed:meshHeading |
pubmed-meshheading:20334367-Animals,
pubmed-meshheading:20334367-Benzamides,
pubmed-meshheading:20334367-Cell Line, Tumor,
pubmed-meshheading:20334367-Cell Proliferation,
pubmed-meshheading:20334367-Drug Screening Assays, Antitumor,
pubmed-meshheading:20334367-Humans,
pubmed-meshheading:20334367-Intracellular Signaling Peptides and Proteins,
pubmed-meshheading:20334367-Mice,
pubmed-meshheading:20334367-Mice, Nude,
pubmed-meshheading:20334367-Models, Molecular,
pubmed-meshheading:20334367-Morpholines,
pubmed-meshheading:20334367-Phenylurea Compounds,
pubmed-meshheading:20334367-Phosphatidylinositol 3-Kinases,
pubmed-meshheading:20334367-Phosphorylation,
pubmed-meshheading:20334367-Protein-Serine-Threonine Kinases,
pubmed-meshheading:20334367-Proto-Oncogene Proteins c-akt,
pubmed-meshheading:20334367-Pyrimidines,
pubmed-meshheading:20334367-Pyrroles,
pubmed-meshheading:20334367-Structure-Activity Relationship,
pubmed-meshheading:20334367-TOR Serine-Threonine Kinases,
pubmed-meshheading:20334367-Transplantation, Heterologous
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pubmed:year |
2010
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pubmed:articleTitle |
Synthesis and SAR of novel 4-morpholinopyrrolopyrimidine derivatives as potent phosphatidylinositol 3-kinase inhibitors.
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pubmed:affiliation |
Chemical Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, New York 10965, USA. chenz1@wyeth.com
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pubmed:publicationType |
Journal Article
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