title: FLT3 kinase inhibitor TTT-3002 overcomes both activating and drug resistance mutations in FLT3 in acute myeloid leukemia.
abstract: There have been a number of clinical trials testing the efficacy of FMS-like tyrosine kinase-3 (FLT3) tyrosine kinase inhibitors (TKI) in patients with acute myeloid leukemia (AML) harboring a constitutively activating mutation in FLT3. However, there has been limited efficacy, most often because of inadequate achievement of FLT3 inhibition through a variety of mechanisms. In a previous study, TTT-3002 was identified as a novel FLT3 inhibitor with the most potent activity to date against FLT3 internal tandem duplication (FLT3/ITD) mutations. Here, the activity of TTT-3002 is demonstrated against a broad spectrum of FLT3-activating point mutations, including the most frequently occurring D835 mutations. The compound is also active against a number of point mutations selected for in FLT3/ITD alleles that confer resistance to other TKIs, including the F691L gatekeeper mutation. TTT-3002 maintains activity against patients with relapsed AML samples that are resistant to sorafenib and AC220. Studies utilizing human plasma samples from healthy donors and patients with AML indicate that TTT-3002 is only moderately protein bound compared with several other TKIs currently in clinical trials. Tumor burden of mice in a FLT3 TKI-resistant transplant model is significantly improved by oral dosing of TTT-3002. Therefore, TTT-3002 has demonstrated preclinical potential as a promising new FLT3 TKI that may overcome some of the limitations of other TKIs in the treatment of FLT3-mutant AML. Cancer Res; 74(18); 5206-17. ©2014 AACR.
authors: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Hayley S
authors: HS
authors: Ma
authors: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Bao
authors: B
authors: Nguyen
authors: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Amy S
authors: AS
authors: Duffield
authors: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Li
authors: L
authors: Li
authors: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Allison
authors: A
authors: Galanis
authors: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Allen B
authors: AB
authors: Williams
authors: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Patrick A
authors: PA
authors: Brown
authors: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Mark J
authors: MJ
authors: Levis
authors: Department of Biophysics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Daniel J
authors: DJ
authors: Leahy
authors: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland. donsmall@jhmi.edu.
authors: Donald
authors: D
authors: Small
mesh_terms: D000818:Animals; D002227:Carbazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004351:Drug Resistance; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*
chemical_list: D002227:Carbazoles; D007211:Indoles; D047428:Protein Kinase Inhibitors; C588240:TTT-3002; C497970:FLT3 protein, human; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3