Mahboobi, Siavosh and Uecker, A. and Sellmer, A. and Cénac, C. and Höcher, H. and Pongratz, H. and Hufsky, H. and Trümpler, A. and Sicker, M. and Heidel, F. and Fischer, T. and Stocking, C. and Elz, Sigurd and Böhmer, F.-D. and Dove, Stefan (2006) Novel bis-(1H-indol-2-yl)-methanones as potent inhibitors of FLT3 and platelet-derived growth factor receptor tyrosine kinase. Journal of Medicinal Chemistry 49 (11), pp. 3101-3115.
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FLT3 receptor tyrosine kinase is aberrantly active in many cases of acute myeloid leukemia (AML). Recently, bis(1H-indol-2-yl)methanones were found to inhibit FLT3 and PDGFR kinases. To optimize FLT3 activity and selectivity, 35 novel derivs. were synthesized and tested for inhibition of FLT3 and PDGFR autophosphorylation. The most potent FLT3 inhibitors I and II show IC50 values of 0.06 and 0.04 mM, resp., and 1 order of magnitude lower PDGFR inhibiting activity. The derivs. III and IV are 20- to 40-fold PDGFR selective. Docking at the recent FLT3 structure suggests a bidentate binding mode with the backbone of Cys-694. Activity and selectivity can be related to interactions of one indole moiety with a hydrophobic pocket including Phe-691, the only different binding site residue (PDGFR Thr-681). Compd. II inhibited the proliferation of 32D cells expressing wildtype FLT3 or FLT3-ITD similarly as FLT3 autophosphorylation, and induced apoptosis in primary AML patient blasts.
|Institutions:|| Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry I (Prof. Elz)
|Projects:||Deutsche Krebshilfe 10-2100|
|Subjects:||500 Science > 570 Life sciences|
500 Science > 540 Chemistry & allied sciences
600 Technology > 610 Medical sciences Medicine
|Refereed:||Yes, this version has been refereed|
|Created at the University of Regensburg:||Partially|
|Owner:||Prof. Dr. Stefan Dove|
|Deposited On:||20 Jan 2009 16:45|
|Last Modified:||05 Aug 2009 13:50|