title: AS602868, a dual inhibitor of IKK2 and FLT3 to target AML cells.
abstract: Acute myeloid leukemia (AML) cells carry molecular defects that promote their leukemic proliferation, resistance to apoptosis and defect in differentiation. Pharmacological targeting of the nuclear factor kappaB (NF-kappaB) pathway has been shown to promote apoptosis of primary AML cells and to sensitize blasts to neoplastic drugs (Frelin, Blood 2005, 105, 804). The Fms-like tyrosine kinase 3 (FLT3), which sustains proliferation of normal hematopoietic progenitors is frequently overexpressed or mutated in AML patients. Using Ba/F3 murine pre-B cells transfected with various mutants of FLT3 (ITD, D835V, D835Y) and the MV4-11 human AML line, we show that normal or oncogenic stimulation of FLT3 led to activation of NF-kappaB. Pharmacological inhibition of either FLT3 with AG1296 or NF-kappaB with the small molecule inhibitor of IkappaB kinase-2 AS602868 reduced viability and triggered cell death. Moreover, AS602868 was also found to interfere directly with FLT3 kinase activation. AS602868 thus appears to target two different kinases that play a crucial role in the pathogenesis of AML, making it particularly attractive as a new therapeutical approach for AML.
authors.affiliation: INSERM, U526, Nice, France.
authors.forename: E
authors.initials: E
authors.lastname: Griessinger
authors.forename: V
authors.initials: V
authors.lastname: Imbert
authors.forename: P
authors.initials: P
authors.lastname: Lagadec
authors.forename: N
authors.initials: N
authors.lastname: Gonthier
authors.forename: P
authors.initials: P
authors.lastname: Dubreuil
authors.forename: A
authors.initials: A
authors.lastname: Romanelli
authors.forename: M
authors.initials: M
authors.lastname: Dreano
authors.forename: J-F
authors.initials: JF
authors.lastname: Peyron
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000032:analysis; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D002648:Child; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051020:bcl-X Protein / Q000032:analysis; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*
chemical_list: C519899:AS602868; D017304:Annexin A5; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D051020:bcl-X Protein; D011065:Poly(ADP-ribose) Polymerases; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D051550:I-kappa B Kinase; D053148:Caspase 3