Mahboobi, Siavosh and Uecker, Andrea and Sellmer, Andreas and Cenac, Christophe and Hoecher, Heymo and Pongratz, Herwig and Eichhorn, Emerich and Hufsky, Harald and Truempler, Antje and Sicker, Marit and Heidel, Florian and Fischer, Thomas and Stocking, Carol and Elz, Sigurd and Boehmer, Frank-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. ISSN 0022-2623, 1520-4804
Full text not available from this repository. (Request a copy)Abstract
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 derivatives were synthesized and tested for inhibition of FLT3 and PDGFR autophosphorylation. The most potent FLT3 inhibitors 98 and 102 show IC50 values of 0.06 and 0.04 mu M, respectively, and 1 order of magnitude lower PDGFR inhibiting activity. The derivatives 76 and 82 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). Compound 102 inhibited the proliferation of 32D cells expressing wildtype FLT3 or FLT3-ITD similarly as FLT3 autophosphorylation, and induced apoptosis in primary AML patient blasts.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CONVENIENT SYNTHESIS; IMATINIB MESYLATE; STRUCTURAL BASIS; LEUKEMIA-CELLS; DOMAIN; ABL; TRANSFORMATION; ANGIOGENESIS; DERIVATIVES; STI-571; |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry I (Prof. Elz) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 15 Feb 2021 09:27 |
| Last Modified: | 15 Feb 2021 09:27 |
| URI: | https://pred.uni-regensburg.de/id/eprint/34503 |
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