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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
5
|
| pubmed:dateCreated |
1996-8-15
|
| pubmed:abstractText |
Wortmannin, a fungal metabolite, was identified as a potent inhibitor (IC50 = 4.2 nM) of phosphatidylinositol 3-kinase (PI 3-kinase). Due to the importance of PI 3-kinase in several intracellular signaling pathways, structure-activities studies on wortmannin analogs were performed in an effort to understand the structural requirements necessary for PI 3-kinase inhibition. Since wortmannin is an irreversible inhibitor of PI 3-kinase, it was postulated that covalent attachment at the electrophilic C-21 site was a possible mode of action for PI 3-kinase inhibition. We have prepared various wortmannin analogs which address the possibility of this mechanism. Of particular interest are compounds which affect the C-21 position of wortaminnin either sterically or electronically. Our results support the conclusion that nucleophilic addition by the kinase onto the C-21 position of wortmannin is required for inhibition of PI 3-kinase by wortmannin analogs. Additionally, we have prepared several D-ring analogs of wortmannin, and their activities are reported herein. We conclude that the wortmannin D ring is an important recognition site since modifications have such a dramatic effect on inhibitor potency. Finally, the identification of 17beta-hydroxywortmannin represents the first reported subnanomolar inhibitor of PI 3-kinase. These studies, along with in vivo antitumor experiments, suggest that the mechanism of PI 3-kinase inhibition correlates to the associated toxicity observed with wortmannin-based inhibitors of PI 3-kinase.
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Androstadienes,
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphatidylinositol 3-Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphotransferases (Alcohol Group...,
http://linkedlifedata.com/resource/pubmed/chemical/wortmannin
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
Mar
|
| pubmed:issn |
0022-2623
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:day |
1
|
| pubmed:volume |
39
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
1106-11
|
| pubmed:dateRevised |
2010-11-18
|
| pubmed:meshHeading |
pubmed-meshheading:8676346-Androstadienes,
pubmed-meshheading:8676346-Animals,
pubmed-meshheading:8676346-Antineoplastic Agents,
pubmed-meshheading:8676346-Crystallography, X-Ray,
pubmed-meshheading:8676346-Enzyme Inhibitors,
pubmed-meshheading:8676346-Humans,
pubmed-meshheading:8676346-Mammary Neoplasms, Experimental,
pubmed-meshheading:8676346-Mice,
pubmed-meshheading:8676346-Models, Molecular,
pubmed-meshheading:8676346-Molecular Conformation,
pubmed-meshheading:8676346-Molecular Structure,
pubmed-meshheading:8676346-Neoplasm Transplantation,
pubmed-meshheading:8676346-Phosphatidylinositol 3-Kinases,
pubmed-meshheading:8676346-Phosphotransferases (Alcohol Group Acceptor),
pubmed-meshheading:8676346-Structure-Activity Relationship,
pubmed-meshheading:8676346-Thermodynamics,
pubmed-meshheading:8676346-Tumor Cells, Cultured
|
| pubmed:year |
1996
|
| pubmed:articleTitle |
Studies on the mechanism of phosphatidylinositol 3-kinase inhibition by wortmannin and related analogs.
|
| pubmed:affiliation |
Eli Lilly and Company, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285, USA.
|
| pubmed:publicationType |
Journal Article
|