Synthesis, structure-activity relationship, and p210(bcr-abl) protein tyrosine kinase activity of novel AG 957 analogs

A series of novel, sterically hindered lipophilic analogs of AG 957 was designed and synthesized as potential protein tyrosine kinase (PTK) inhibitors. The in vitro activity, in vivo anti-leukemia activity, and pharmacology of these PTK inhibitors were studied. Some aspects of the structure-activity...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2005-03, Vol.13 (5), p.1749
Main Authors: Kaur, Gurmeet, Narayanan, Ven L, Risbood, Prabhakar A, Hollingshead, Melinda G, Stinson, Sherman F, Varma, Ravi K, Sausville, Edward A
Format: Article
Language:English
Subjects:
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacokinetics
Enzyme Inhibitors - pharmacology
Fusion Proteins, bcr-abl
Protein-Tyrosine Kinases - metabolism
Structure-Activity Relationship
Tyrphostins - chemistry
Tyrphostins - pharmacokinetics
Tyrphostins - pharmacology
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Summary:A series of novel, sterically hindered lipophilic analogs of AG 957 was designed and synthesized as potential protein tyrosine kinase (PTK) inhibitors. The in vitro activity, in vivo anti-leukemia activity, and pharmacology of these PTK inhibitors were studied. Some aspects of the structure-activity relationship associated with the carboxylic acid, phenol ring, and linker modifications are discussed. We have demonstrated that the 1,4-hydroquinone moiety is essential for activity and that sterically hindered esters contribute to enhanced in vivo efficacy. Adaphostin (NSC 680410) has emerged as the improved compound with the maximum in vivo anti-leukemia hollow fiber activity, concordant with the original lead compound AG 957. Currently, adaphostin is undergoing preclinical toxicology studies.
ISSN:0968-0896
DOI:10.1016/j.bmc.2004.12.003