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

Patrick P. Zarrinkar*, Ruwanthi N. Gunawardane,Merryl D. Cramer, Michael F. Gardner, Daniel Brigham, Barbara Belli, Mazen W. Karaman, Keith W. Pratz, Gabriel Pallares, Qi Chao, Kelly G. Sprankle, Hitesh K. Patel, Mark Levis, Robert C. Armstrong, Joyce James, and Shripad S. Bhagwat

Abstract:

Activating mutations in the receptor tyrosine kinase FLT3 are present in up to approximately 30% of 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 to the first generation FLT3 inhibitors CEP-701, MLN-518, PKC-412, sorafenib and sunitinib. AC220 exhibits low nanomolar potency in biochemical and cellular assays, 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.