Quizartinib

Quizartinib (AC220) is a potent, selective, second-generation FLT3 inhibitor with Kd of 1.6 nM, inhibits Wt FLT3 and FLT3-ITD autophosphorylation in MV4-11cell with IC50 of 4.2 and 1.1 nM, respectively; displays excellent kinase selectivity in a KinomeScan panel of 402 kinase binding assays, also potently inhibits PDGFRA, PDGFRB and RET; inhibits MV4-11 cell proliferarion with IC50 of 0.56 nM, demonstrates antitumor efficacy in the MV4-11 tumor xenograft model.Blood Cancer Phase 3 Clinical(In Vitro):Quizartinib (AC220) is a novel compound expressly optimized as a FLT3 inhibitor for the treatment of acute myeloid leukemia (AML). Quizartinib inhibits FLT3-WT and FLT3-ITD autophosphorylation with IC50 of 4.2±0.3 nM and 1.1±0.1 nM, respectively. Quizartinib inhibits MV4-11 and A375 cells with IC50 of 0.56±0.3 nM and >10 000 nM, respectively. Quizartinib inhibits FLT3 with low nanomolar potency in cellular assays and is highly selective when screened against the majority of the human protein kinome.(In Vivo):Quizartinib (AC220) inhibits FLT3 activity in vivo, significantly extends survival in a mouse model of FLT3-ITD AML at doses as low as 1 mg/kg when dosed orally once a day, 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%. A single 10 mg/kg dose of Quizartinib is administered by oral gavage, and mice are killed at 2 time points after dosing, using groups of 4 animals each. Quantitation of total FLT3 and phospho-FLT3 in tumor samples revealed time-dependent inhibition of FLT3 autophosphorylation. FLT3 activity is inhibited by 90% at 2 hours, and 40% at 24 hours after administration. The extent of inhibition therefore correlated well with the expected free Quizartinib plasma levels, based on pharmacokinetic experiments.