期刊
BLOOD
卷 114, 期 14, 页码 2984-2992出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2009-05-222034
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资金
- National Cancer Institute (NCI) [P50 CA100632-06, R01 CA128864]
- American Society of Clinical Oncology
- Clinical Scholar of the Leukemia & Lymphoma Society
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 nano-molar 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. (Blood. 2009; 114: 2984-2992)
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