Cat. No. Name Size Price Add Cart
KI0199AC2205 mg$300
AC22010 mg$500
AC22050 mg$1552
AC220200 mg$3952

Chemical Characteristic

Product NameAC220
SynonymsQuizartinib
CAS No.950769-58-1
Molecular Weight 560.67
FormulaC29H32N6O4S
Chemical NameN-(5-tert-Butylisoxazol-3-yl)-N'-{4-[7-(2-morpholin-4-ylethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea
SmilesN(C(=O)Nc1ccc(cc1)c1nc2sc3c(n2c1)ccc(c3)OCCN1CCOCC1)c1noc(c1)C(C)(C)C
Chemical Structure

Biological activities

AC220 is a unique, potent and selective inhibitor of fms-like tyrosine kinase (FLT3) with IC50 values of 1.1 and 4.2 nM for internal tandem duplications mutation FLT3 (FLT3-ITD) and wild type FLT3 (FLT3-WT) autophosphorylation, respectively. AC220 has high binding affinity for FLT3 with a Kd value of 1.6 nM. The IC50 value of AC220 is 0.56 nM in the human leukemia cell line MV4-11 which harbors a homozygous FLT3-ITD mutation and is FLT3 dependent. AC220 activity against blast cells from 4 patients harboring FLT3-ITD mutations has IC50 values ranging from 0.8 to 2 nM, comparable with the activity observed in the MV4-11 cell line.[1] Besides, Ba/F3 cells dependent on the expression of FLT3-ITD with additional N676D, F691I, F691L, or G697R mutants confer resistance to AC220, with G697R and F691L/I mutations being the most resistant, and N676D conferring a lower level of resistance.[2] Oral administration of AC220 (10 mg/kg) to mice, AC220 achieves a maximum plasma level (Cmax) of 3.8 µM (2100 ng/mL) within 2 hours of dosing. In the FLT3-ITD??ependent MV4-11 tumor xenograft model, AC220 (10 mg/kg) induces time-dependent inhibition of FLT3 autophosphorylation. AC220 inhibits FLT3 activity by 90% at 2 hours, and 40% at 24 hours after administration. Furthermore, in MV4-11 tumor xenograft model, AC220 (10 mg/kg) results in rapid and complete regression of tumors in all animals, and no tumor regrowth is observed during the 60-day posttreatment observation period. There is no weight loss or any other obvious signs of toxicity after AC220 treatment. In a mouse bone marrow engraftment model, AC220 (0.1-10 mg/kg) prolongs survival in a dose-dependent manner.[1]

Protocols

AC220 (hydrochloride salt) is formulated in 22% hydroxypropyl-β-cyclodextrin. [1]

References

[1] Zarrinkar PP, et al. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood. 2009, 114(14): 2984-2992
[2] Pauwels D, et al. The N676D and G697R mutations in the kinase domain of FLT3 confer resistance to the inhibitor AC220. Haematologica. 2012.
[3] Fabian MA, et al. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol. 2005, 23(3): 329-336.

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