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 μM. A combinatorial synthesis approach enabled the identification of a breakthrough lead (IC50=0.54 μM) for a second generation series of heterocyclic urea raf kinase inhibitors.