title: Transient exposure to quizartinib mediates sustained inhibition of FLT3 signaling while specifically inducing apoptosis in FLT3-activated leukemia cells.
abstract: Fms-like tyrosine kinase 3 (FLT3) is implicated in the pathogenesis of acute myeloid leukemia (AML). FLT3-activating internal tandem duplication (ITD) mutations are found in approximately 30% of patients with AML and are associated with poor outcome in this patient population. Quizartinib (AC220) has previously been shown to be a potent and selective FLT3 inhibitor. In the current study, we expand on previous observations by showing that quizartinib potently inhibits the phosphorylation of FLT3 and downstream signaling molecules independent of FLT3 genotype, yet induces loss of viability only in cells expressing constitutively activated FLT3. We further show that transient exposure to quizartinib, whether in vitro or in vivo, leads to prolonged inhibition of FLT3 signaling, induction of apoptosis, and drastic reductions in tumor volume and pharmacodynamic endpoints. In vitro experiments suggest that these prolonged effects are mediated by slow binding kinetics that provide for durable inhibition of the kinase following drug removal/clearance. Together these data suggest quizartinib, with its unique combination of selectivity and potent/sustained inhibition of FLT3, may provide a safe and effective treatment against FLT3-driven leukemia.
authors: Ambit Biosciences, Corp, 11080 Roselle St., San Diego, CA 92121, USA.
authors: Ruwanthi N
authors: RN
authors: Gunawardane
authors: Ronald R
authors: RR
authors: Nepomuceno
authors: Allison M
authors: AM
authors: Rooks
authors: Jeremy P
authors: JP
authors: Hunt
authors: Jill M
authors: JM
authors: Ricono
authors: Barbara
authors: B
authors: Belli
authors: Robert C
authors: RC
authors: Armstrong
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D052160:Benzothiazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D007938:Leukemia / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D015398:Signal Transduction / Q000187:drug effects*; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism*
chemical_list: D052160:Benzothiazoles; D010671:Phenylurea Compounds; C544967:quizartinib; D051941:fms-Like Tyrosine Kinase 3