AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML)

Blood. 2009 Oct 1;114(14):2984-92. doi: 10.1182/blood-2009-05-222034. Epub 2009 Aug 4.

Abstract

Activating mutations in the receptor tyrosine kinase FLT3 are present in up to approximately 30% of acute myeloid leukemia (AML) patients, implicating FLT3 as a driver of the disease and therefore as a target for therapy. We report the characterization of AC220, a second-generation FLT3 inhibitor, and a comparison of AC220 with the first-generation FLT3 inhibitors CEP-701, MLN-518, PKC-412, sorafenib, and sunitinib. AC220 exhibits low nanomolar potency in biochemical and cellular assays and exceptional kinase selectivity, and in animal models is efficacious at doses as low as 1 mg/kg given orally once daily. The data reveal that the combination of excellent potency, selectivity, and pharmacokinetic properties is unique to AC220, which therefore is the first drug candidate with a profile that matches the characteristics desirable for a clinical FLT3 inhibitor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzenesulfonates / pharmacology
  • Benzothiazoles / pharmacokinetics
  • Benzothiazoles / pharmacology*
  • Bone Marrow / drug effects
  • Bone Marrow / pathology
  • Carbazoles / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Female
  • Furans
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Mice
  • Mice, Nude
  • Mice, SCID
  • Niacinamide / analogs & derivatives
  • Phenylurea Compounds / pharmacokinetics
  • Phenylurea Compounds / pharmacology*
  • Phosphorylation / drug effects
  • Piperazines / pharmacology
  • Prognosis
  • Protein Interaction Mapping
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Pyridines / pharmacology
  • Quinazolines / pharmacology
  • Sorafenib
  • Staurosporine / analogs & derivatives
  • Staurosporine / pharmacology
  • Xenograft Model Antitumor Assays
  • fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*

Substances

  • Benzenesulfonates
  • Benzothiazoles
  • Carbazoles
  • Furans
  • Phenylurea Compounds
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyridines
  • Quinazolines
  • Niacinamide
  • quizartinib
  • Sorafenib
  • lestaurtinib
  • tandutinib
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3
  • Protein Kinase C
  • Staurosporine
  • midostaurin