Quizartinib (AC220) is a potent second generation class III tyrosine kinase inhibitor that displays a distinct inhibition profile against mutant-FLT3, -PDGFRA and -KIT isoforms

Table 3 Estimated IC50s for the proapoptotic and antiproliferative effects of quizartinib in an isogenic cell model of Ba/F3 cells transfected with various mutant TKs

Isoform	Mutation locus	IC50 (nM)	IC50 (nM)	IC50 (nM)	IC50 (nM)
		*Ba/F3 transfectants*		*leukemia cell lines*
		*Inhibition of proliferation*	*Induction of apotosis*	*Inhibition of proliferation*	*Induction of apotosis*
BCR/ABL	fusion	n.r.*	n.r.*	not reached (K562)	n.r.* (K562)
FLT3 WT	N/A	49	11
FLT3 ITD, 10% FBS	juxtamembrane domain	9	5	<1 (MOLM14)	3 (MOLM14)
FLT3 ITD, 0.5%FBS	juxtamembrane domain	<1	N/D
FLT3 K663Q	tyrosine kinase domain I	14	23
FLT D835V	tyrosine kinase domain II	172	888
FLT3 D835Y	tyrosine kinase domain II	84	24
KIT WT	N/A	474	n.r.*	77 (M0-7e)	210 (MO-7e)
KIT D816F	tyrosine kinase domain II	2871	6254
KIT D816V, 10% FBS	tyrosine kinase domain II	3074	8982	1727 (HMC1.2)	n.r.* (HMC1.2)
KIT D816V, 0.5% FBS	tyrosine kinase domain II	633	N/A
KIT D816Y, 0.5% FBS	tyrosine kinase domain II	366	611	445 (p815)	341 (p815)
parental	N/A	n.r.*	n.r.*
parental + DMSO	N/A	n.r.*	n.r.*

*(not reached with tested doses up to 10 000 nM).
Sensitivity of quizartinib is distinct to and differs widely in between different tyrosine kinase isoforms transfected into an isogenic Ba/F3 cellular background. Estimated IC50s were computed using non-linear regression analysis of an average mean of at least 3 experiments for each cell line.
If applicable, IC50s of leukemic cell lines harboring a similar mutation are provided (rows on the right).
Influence of serum-deprivation on sensitivity profiles of quizartinib was tested in two cell strains (Ba/F3 FLT3 ITD or KIT D816V): Cells were cultured in media with a reduced serum concentration (0.5% FBS) and treated with quizartinib the next day.
Solvent-associated non-specific cytotoxicity was excluded using the parental Ba/F3 cell strain treated with DMSO in the highest concentration used for the quizartinib dose experiments.

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