Quizartinib (AC220) inhibits FLT3 activity in vivo, significantly prolonging survival in a mouse model of FLT3-ITD AML at doses as low as 1 mg/kg when administered orally once daily. It eradicates tumors in a FLT3-dependent mouse xenograft model at 10 mg/kg and potently inhibits FLT3 activity in primary patient cells. The oral bioavailability of Quizartinib, determined in rats by comparing oral and intravenous pharmacokinetics at 3 mg/kg, is approximately 40%. Following administration of a single 10 mg/kg dose of Quizartinib via oral gavage, mice are euthanized at 2 time points after dosing, with groups of 4 animals each. Quantification of total FLT3 and phospho-FLT3 in tumor samples reveals time-dependent inhibition of FLT3 autophosphorylation. FLT3 activity is inhibited by 90% at 2 hours and 40% at 24 hours post-administration. The degree of inhibition correlates well with the expected free Quizartinib plasma levels, as determined by pharmacokinetic experiments^[1].

Quizartinib (AC220) is a newly developed compound specifically optimized as a FLT3 inhibitor for the treatment of acute myeloid leukemia (AML). It effectively inhibits FLT3-WT and FLT3-ITD autophosphorylation, with IC50 values of 4.2±0.3 nM and 1.1±0.1 nM, respectively. Furthermore, Quizartinib demonstrates inhibition of MV4-11 and A375 cells, with IC50 values of 0.56±0.3 nM and >10,000 nM, respectively. In cellular assays, Quizartinib displays potent inhibition of FLT3 at low nanomolar concentrations and exhibits high selectivity when screened against the majority of the human protein kinome^[1].