tandutinib and quizartinib

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.

Topics: Animals; Benzenesulfonates; Benzothiazoles; Bone Marrow; Carbazoles; Cell Line, Tumor; Cell Proliferation; Female; fms-Like Tyrosine Kinase 3; Furans; Humans; Leukemia, Myeloid, Acute; Mice; Mice, Nude; Mice, SCID; Niacinamide; Phenylurea Compounds; Phosphorylation; Piperazines; Prognosis; Protein Interaction Mapping; Protein Kinase C; Protein Kinase Inhibitors; Pyridines; Quinazolines; Sorafenib; Staurosporine; Xenograft Model Antitumor Assays