Linked Life Data

9513602

Source:http://linkedlifedata.com/resource/pubmed/id/9513602

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
1998-4-14
pubmed:abstractText
The 4-[(3-bromophenyl)amino]pyrido[3,4-d]pyrimidine PD 158780 is a very potent in vitro inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) (IC50 0.08 nM), and other members of the erbB family, by competitive binding at the ATP site of these signal transduction enzymes. A series of analogues of PD 158780 bearing solubilizing functions off the 6-methylamino substituent were prepared by reaction of the 6-fluoro derivatives with appropriate amine nucleophiles. These were evaluated for their ability to inhibit the tyrosine phosphorylating action of EGF-stimulated full-length EGFR enzyme and for inhibition of autophosphorylation of the EGFR in A431 human epidermoid carcinoma cells in culture. The most effective analogues were those bearing weakly basic substituents through a secondary amine linkage, which proved water-soluble (> 10 mM) and potent (IC50S generally < 1 nM). No clear SAR could be discerned for these compounds with respect to amine base strength or the distance of the cationic center from the chromophore, suggesting that 6-substituents are in a favorable area of bulk tolerance in the enzyme binding site. More distinct SAR emerged for the ability of the compounds to inhibit EGFR autophosphorylation in A431 cells, where analogues bearing lipophilic weak bases were preferred. Representative analogues were evaluated for antitumor effectiveness against four in vivo tumor models. Significant in vivo activity was observed in estrogen-dependent MCF-7 breast and A431 epidermoid tumors. Marginal activity was seen in an EGFR-transfected tumor model, suggesting that while this cell line requires EGF for clone formation in soft agar, other growth factors may be able to replace EGF in vivo. Also, no activity was seen against the SK-OV-3 ovarian cancer model, which is known to express other EGF receptor family members (although it is not clear whether these are absolutely required for growth in vivo). While substantial growth delays were seen in A431 and MCF-7 tumor models, the treated tumors remained approximately the same size throughout therapy, suggesting that the compounds are cytostatic rather than cytotoxic under these test conditions. It remains to be determined if more prolonged therapy has cytotoxic effects in vivo, resulting in net tumor cell kill.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
26
pubmed:volume
41
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
742-51
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:9513602-3T3 Cells, pubmed-meshheading:9513602-Animals, pubmed-meshheading:9513602-Antineoplastic Agents, pubmed-meshheading:9513602-Breast Neoplasms, pubmed-meshheading:9513602-Carcinoma, Squamous Cell, pubmed-meshheading:9513602-Enzyme Inhibitors, pubmed-meshheading:9513602-Female, pubmed-meshheading:9513602-Humans, pubmed-meshheading:9513602-Mice, pubmed-meshheading:9513602-Mice, Nude, pubmed-meshheading:9513602-Molecular Structure, pubmed-meshheading:9513602-Ovarian Neoplasms, pubmed-meshheading:9513602-Phosphorylation, pubmed-meshheading:9513602-Protein-Tyrosine Kinases, pubmed-meshheading:9513602-Pyrimidines, pubmed-meshheading:9513602-Receptor, Epidermal Growth Factor, pubmed-meshheading:9513602-Receptor Protein-Tyrosine Kinases, pubmed-meshheading:9513602-Structure-Activity Relationship, pubmed-meshheading:9513602-Transfection, pubmed-meshheading:9513602-Tumor Cells, Cultured
pubmed:year
1998
pubmed:articleTitle
Tyrosine kinase inhibitors. 14. Structure-activity relationships for methylamino-substituted derivatives of 4-[(3-bromophenyl)amino]-6-(methylamino)-pyrido[3,4-d]pyrimidine (PD 158780), a potent and specific inhibitor of the tyrosine kinase activity of receptors for the EGF family of growth factors.
pubmed:affiliation
Cancer Society Research Laboratory, Faculty of Medicine and Health Science, University of Auckland, New Zealand.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't