AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML)
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Open Access
- 1 October 2009
- journal article
- Published by American Society of Hematology in Blood
- Vol. 114 (14), 2984-2992
- https://doi.org/10.1182/blood-2009-05-222034
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.Keywords
This publication has 52 references indexed in Scilit:
- A pharmacodynamic study of the FLT3 inhibitor KW-2449 yields insight into the basis for clinical responseBlood, 2009
- Antileukemic effects of the novel, mutant FLT3 inhibitor NVP-AST487: effects on PKC412-sensitive and -resistant FLT3-expressing cellsBlood, 2008
- Patterns of somatic mutation in human cancer genomesNature, 2007
- ABT-869, a multitargeted receptor tyrosine kinase inhibitor: inhibition of FLT3 phosphorylation and signaling in acute myeloid leukemiaBlood, 2007
- Clinical implications of FLT3 mutations in pediatric AMLBlood, 2006
- Phase 1 clinical results with tandutinib (MLN518), a novel FLT3 antagonist, in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome: safety, pharmacokinetics, and pharmacodynamicsBlood, 2006
- Plasma inhibitory activity (PIA): a pharmacodynamic assay reveals insights into the basis for cytotoxic response to FLT3 inhibitorsBlood, 2006
- FLT3 internal tandem duplication in CD34+/CD33- precursors predicts poor outcome in acute myeloid leukemiaBlood, 2006
- EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib TherapyScience, 2004
- Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non–Small-Cell Lung Cancer to GefitinibThe New England Journal of Medicine, 2004