title: Bis(1H-2-indolyl)-1-methanones as inhibitors of the hematopoietic tyrosine kinase Flt3.
abstract: Aberrant expression and activating mutations of the class III receptor tyrosine kinase Flt3 (Flk-2, STK-1) have been linked to poor prognosis in acute myeloid leukemia (AML). Inhibitors of Flt3 tyrosine kinase activity are, therefore, of interest as potential therapeutic compounds. We previously described bis(1H-2-indolyl)-1-methanones as a novel class of selective inhibitors for platelet-derived growth factor receptors (PDGFR). Several bis(1H-2-indolyl)-1-methanone derivatives, represented by the compounds D-64406 and D-65476, are also potent inhibitors of Flt3. They inhibit proliferation of TEL-Flt3-transfected BA/F3 cells with IC(50) values of 0.2-0.3 microM in the absence of IL-3 but >10 microM in the presence of IL-3. Ligand-stimulated autophosphorylation of Flt3 in EOL-1 cells and corresponding downstream activation of Akt/PKB are effectively inhibited by bis(1H-2-indolyl)-1-methanones whereas autophosphorylation of c-Kit/SCF receptor or c-Fms/CSF-1 receptor is less sensitive or insensitive, respectively. Flt3 kinase purified by different methods is potently inhibited in vitro, demonstrating a direct mechanism of inhibition. 32D cells, expressing a constitutively active Flt3 variant with internal tandem duplication are greatly sensitized to radiation-induced apoptosis in the presence of D-64406 or D-65476 in the absence but not in the presence of IL-3. Thus, bis(1H-2-indolyl)-1-methanones are potential candidates for the treatment of Flt3-driven leukemias.
authors.affiliation: Research Unit Molecular Cell Biology, Medical Faculty, Friedrich Schiller University, Jena, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Teller
authors.forename: D
authors.initials: D
authors.lastname: Krämer
authors.forename: S-A
authors.initials: SA
authors.lastname: Böhmer
authors.forename: K F
authors.initials: KF
authors.lastname: Tse
authors.forename: D
authors.initials: D
authors.lastname: Small
authors.forename: S
authors.initials: S
authors.lastname: Mahboobi
authors.forename: C
authors.initials: C
authors.lastname: Wallrapp
authors.forename: T
authors.initials: T
authors.lastname: Beckers
authors.forename: K
authors.initials: K
authors.lastname: Kratz-Albers
authors.forename: J
authors.initials: J
authors.lastname: Schwäble
authors.forename: H
authors.initials: H
authors.lastname: Serve
authors.forename: F-D
authors.initials: FD
authors.lastname: Böhmer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000077214:Becaplermin; D002461:Cell Line, Transformed / Q000187:drug effects / Q000201:enzymology; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000201:enzymology*; D007211:Indoles / Q000494:pharmacology*; D007377:Interleukin-3 / Q000494:pharmacology; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000201:enzymology; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D051941:fms-Like Tyrosine Kinase 3
chemical_list: D000970:Antineoplastic Agents; C463259:D-64406; C463260:D-65476; D004791:Enzyme Inhibitors; D007211:Indoles; D007377:Interleukin-3; D015514:Oncogene Proteins, Fusion; D010982:Platelet-Derived Growth Factor; D011518:Proto-Oncogene Proteins; D020574:Proto-Oncogene Proteins c-sis; D011993:Recombinant Fusion Proteins; C463241:TEL-Flt3 fusion protein, mice; D000077214:Becaplermin; C497971:Flt3 protein, mouse; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases; D016186:Receptor, Macrophage Colony-Stimulating Factor; D020797:Receptor, Platelet-Derived Growth Factor beta; D051941:fms-Like Tyrosine Kinase 3; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt