Inhibition of FLT3 and PDGFR tyrosine kinase activity by bis(benzo[b]furan-2-yl)methanones.
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 derivative. The 5,5'-diamino and the 6,6'-dihydroxy compounds are more active at FLT3. At both kinases, the potency of the best inhibitors approaches IC50 values of ca. 0.5 microM. Molecular modeling studies suggest that the bisbenzofuranylmethanones are able to fit into the same binding site as their indolyl analogues 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.
Mahboobi
Siavosh
S
Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, D-93040 Regensburg, Germany. siavosh.mahboobi@chemie.uni-regensburg.de
Uecker
Andrea
A
Cénac
Christophe
C
Sellmer
Andreas
A
Eichhorn
Emerich
E
Elz
Sigurd
S
Böhmer
Frank-D
FD
Dove
Stefan
S
D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005663:Furans / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D021241:Spectrometry, Mass, Electrospray Ionization; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D005663:Furans; C497971:Flt3 protein, mouse; D017479:Receptors, Platelet-Derived Growth Factor; D051941:fms-Like Tyrosine Kinase 3