Switch to
| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
8
|
| pubmed:dateCreated |
1991-9-25
|
| pubmed:abstractText |
The synthesis and biological activities of a series of sulfonylbenzoyl-nitrostyrene derivatives, a novel class of selective bisubstrate type inhibitors of the EGF-receptor tyrosine protein kinase, are described. The most potent derivatives inhibited the EGF-R tyrosine kinase, using angiotensin II as exogenous substrate, with IC50 values of less than or equal to 1 microM. No inhibition of the v-abl tyrosine kinase or the serine/threonine kinases PKC and PK-A was observed. In addition, active derivatives (compounds 5 and 12) effectively blocked the autophosphorylation of the EGF-R in vitro. Starting from the acids 5, 7, and 9, a series of esters, amides, and peptides was synthesized with the aim of increasing cellular penetration. Amides 14-18 showed potent antiproliferative effects using the EGF-dependent Balb/MK mouse epidermal keratinocyte cell line. Additionally, with the amide 14 inhibition of EGF-R autophosphorylation was demonstrated in the A431 cell line. CAMM studies using a computer-generated model for the transition state of the gamma-phosphoryl transfer from ATP to a tyrosine moiety and fitting experiments using the highly potent derivative 7 (IC50 value = 54 nM) support the hypothesis that the sulfonylbenzoyl group mimics a diphosphate moiety in the transition state. These results demonstrate that the rational design of tyrosine kinase inhibitors, using the inhibitory nitrostyrene moiety as a tyrosine mimic together with the sulfonylbenzoyl moiety as a diphosphate mimic, leads to highly potent and selective multisubstrate type inhibitors.
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Angiotensin II,
http://linkedlifedata.com/resource/pubmed/chemical/Benzoates,
http://linkedlifedata.com/resource/pubmed/chemical/Epidermal Growth Factor,
http://linkedlifedata.com/resource/pubmed/chemical/Nitro Compounds,
http://linkedlifedata.com/resource/pubmed/chemical/Protein-Tyrosine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor, Epidermal Growth Factor,
http://linkedlifedata.com/resource/pubmed/chemical/Styrenes,
http://linkedlifedata.com/resource/pubmed/chemical/Sulfones
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
Aug
|
| pubmed:issn |
0022-2623
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:volume |
34
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
2328-37
|
| pubmed:dateRevised |
2009-11-19
|
| pubmed:meshHeading |
pubmed-meshheading:1652014-Angiotensin II,
pubmed-meshheading:1652014-Animals,
pubmed-meshheading:1652014-Benzoates,
pubmed-meshheading:1652014-Cell Division,
pubmed-meshheading:1652014-Cell Line,
pubmed-meshheading:1652014-Chemical Phenomena,
pubmed-meshheading:1652014-Chemistry,
pubmed-meshheading:1652014-Computer Simulation,
pubmed-meshheading:1652014-Crystallography,
pubmed-meshheading:1652014-Enzyme Activation,
pubmed-meshheading:1652014-Epidermal Growth Factor,
pubmed-meshheading:1652014-Keratinocytes,
pubmed-meshheading:1652014-Mice,
pubmed-meshheading:1652014-Models, Molecular,
pubmed-meshheading:1652014-Molecular Structure,
pubmed-meshheading:1652014-Nitro Compounds,
pubmed-meshheading:1652014-Phosphorylation,
pubmed-meshheading:1652014-Protein-Tyrosine Kinases,
pubmed-meshheading:1652014-Receptor, Epidermal Growth Factor,
pubmed-meshheading:1652014-Styrenes,
pubmed-meshheading:1652014-Sulfones
|
| pubmed:year |
1991
|
| pubmed:articleTitle |
Sulfonylbenzoyl-nitrostyrenes: potential bisubstrate type inhibitors of the EGF-receptor tyrosine protein kinase.
|
| pubmed:affiliation |
Oncology and Virology Research Department, Ciba-Geigy Ltd., Basel, Switzerland.
|
| pubmed:publicationType |
Journal Article
|