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 IC50 = 1.7 muM. A combinatorial synthesis approach enabled the identification of a breakthrough lead (IC50 = 0.54 muM) for a second generation series of heterocyclic urea raf kinase inhibitors. (C) 2001 Elsevier Science Ltd. All rights reserved.