Design and discovery of 4-anilinoquinazoline ureas as multikinase inhibitors targeting BRAF, VEGFR-2 and EGFR,10.1039/C3MD00096F

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Design and discovery of 4-anilinoquinazoline ureas as multikinase inhibitors targeting BRAF, VEGFR-2 and EGFR

Qingwen Zhang,Yuanyuan Diao,Fei Wang,Ying Fu,Fei Tang,Qidong You,Houyuan Zhou

MedChemComm Pub Date : 05/01/2013 00:00:00 , DOI:10.1039/C3MD00096F

Abstract

4-Anilinoquinazoline ureas were envisaged according to the hybrid-design approach based upon two privileged pharmacophores in kinase drug discovery, i.e. 4-anilinoquinazoline and unsymmetrical diaryl urea. In our structure–activity relationships (SAR) campaign, title compounds were synthesized and profiled in biochemical assay for their kinase inhibitory activity. Title compounds 18–20 were found to be multikinase inhibitors with profound activity against BRAF, BRAF V600E, VEGFR-2 and EGFR. Molecular docking into DFG-out conformations of BRAF and VEGFR-2 suggested that they might be type II inhibitors.