Discovery of heterocyclic ureas as a new class of raf kinase inhibitors: identification of a second generation lead by a combinatorial chemistry approach

Heterocyclic ureas, such as N-3-thienyl N′-aryl ureas, have been identified as novel inhibitors of raf kinase, a key mediator in the ras signal transduction pathway. Structure–activity relationships were established, and the potency of the screening hit was improved 10-fold to IC 50=1.7 μM. A combin...

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Bibliographic Details
Published in:	Bioorganic & medicinal chemistry letters Vol. 11; no. 20; pp. 2775 - 2778
Main Authors:	Smith, Roger A, Barbosa, James, Blum, Cheri L, Bobko, Mark A, Caringal, Yolanda V, Dally, Robert, Johnson, Jeffrey S, Katz, Michael E, Kennure, Nancy, Kingery-Wood, Jill, Lee, Wendy, Lowinger, Timothy B, Lyons, John, Marsh, Vivienne, Rogers, Daniel H, Swartz, Stephen, Walling, Tracy, Wild, Hanno
Format:	Journal Article
Language:	English
Published:	Oxford Elsevier Ltd 22-10-2001 Elsevier
Subjects:	Antineoplastic agents Biological and medical sciences General aspects Medical sciences Pharmacology. Drug treatments Proto-Oncogene Proteins c-raf - antagonists & inhibitors Structure-Activity Relationship Urea - analogs & derivatives Urea - chemical synthesis Urea - chemistry Urea - pharmacology Antineoplastic agent Automation Isoxazole derivatives Enzyme Transferases Combinatorial chemistry Enzyme inhibitor In vitro Signal transduction Structure activity relation Kinase Chemical compound library Benzenic compound Ureas Onc gene Chemical synthesis Oxygen nitrogen heterocycle
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Summary:	Heterocyclic ureas, such as N-3-thienyl N′-aryl ureas, have been identified as novel inhibitors of raf kinase, a key mediator in the ras signal transduction pathway. Structure–activity relationships were established, and the potency of the screening hit was improved 10-fold to IC 50=1.7 μM. A combinatorial synthesis approach enabled the identification of a breakthrough lead (IC 50=0.54 μM) for a second generation series of heterocyclic urea raf kinase inhibitors. Heterocyclic ureas have been identified as novel inhibitors of raf kinase, and structure–activity relationships were established. The potency of the screening hit was improved 10-fold to IC 50=1.7 μM, whereas a combinatorial synthesis approach enabled the identification of a breakthrough lead (IC 50=0.54 μM) for a second generation series of inhibitors.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0960-894X 1464-3405
DOI:	10.1016/S0960-894X(01)00571-6