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. (Blood. 2009; 114:2984-2992)
IntroductionThe presence of genetic changes in cancer cells that lead to dysregulated activation of kinases frequently signals that the activated kinase is a contributing driver of disease, 1-4 and inhibitors of activated kinases can have a dramatic impact on disease progression in patients with these genetic alterations. 5,6 To clearly define the role of the dysregulated kinase, and to determine whether inhibition of the mutant kinase is sufficient to induce a therapeutic benefit, requires drugs capable of selectively, potently, and preferably sustainably inhibiting the activated kinase in patients.Activating mutations in the FLT3 receptor tyrosine kinase have been identified in up to 30% of acute myeloid leukemia (AML) patients. 7,8 The most common class of mutation is internal tandem duplications (ITDs) in the juxtamembrane domain 7,9 that lead to constitutive, ligand-independent activation of the kinase. 7,10 The prognosis for patients with FLT3-ITD mutations is significantly worse than that for patients with wild-type FLT3 when treated with standard therapy. [7][8][9][11][12][13][14][15][16] The presence of activating FLT3 mutations and the correlation of FLT3 activation with a poor prognosis strongly suggest that FLT3 is a driver of disease in AML, at least in patients with FLT3-ITD mutations. Several small molecule kinase inhibitors with activity against FLT3 have been evaluated in AML patients, including CEP-701 (lestaurtinib), PKC-412 (midostaurin), MLN-518 (tandutinib; previously known as CT-53518), sunitinib (SU-11248), sorafenib , and KW-2449. The compounds inhibit FLT3 in cellular assays and are efficacious in mouse models of FLT3-ITD AML. [17][18][19][20][21][22] In phase 1 and phase 2 clinical trials, conducted primarily in relapsed or refractory AML patients, responses were consistently observed with each of these drugs, 21,[23][24][25][26][27][28][29][30][31] however, responses generally were relatively limited and not durable. 21,[23][24][25]30 The studies did reveal a relationship between the likelihood of observing a clinical response and the pharmacokinetics/pharmacodynamics of FLT3 inhibition, and highlight...