Inhibition of FLT3 and PDGFR tyrosine kinase activity by bis(benzo[b]furan-2-yl)methanones

Abstract

A series of bis(benzo[b]furan-2-yl)methanones was synthesized and tested for inhibition of FLT3 and PDGFR autophosphorylation. Mostly, C-5 substitution leads to PDGFR selectivity, which was strongest in the case of the 5,5'-dimethoxy deriv. The 5,5'-diamino and the 6,6'-dihydroxy compds. are more active at FLT3. At both kinases, the potency of the best inhibitors approaches IC50 values of .apprx.0.5 mM. Mol. modeling studies suggest that the bisbenzofuranylmethanones are able to fit into the same binding site as their indolyl analogs which have been suggested to form a bidentate hydrogen bridge with the backbone in the hinge regions. The loss of one H bond by the NH-O exchange might be partially compensated by, for example, the weak interaction of one furanyl oxygen with FLT3 Cys-828.