N-(5-tert-Butylisoxazol-3-yl)-N'-{4-[7-(2-morpholin-4-ylethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea

Biological activity

Quizartinib (AC220) is a second-generation FLT3 inhibitor for Flt3(ITD/WT) with IC50 of 1.1 nM/4.2 nM in MV4-11 and RS4;11 cells, respectively, 10-fold more selective for Flt3 than KIT, PDGFRα, PDGFRβ, RET, and CSF-1R. Phase 3.

In vitro

AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). AC220 exhibits low nanomolar potency in biochemical and cellular assays and exceptional kinase selectivity high selectivity, but high selectivity when inhibiting most protein kinase of the human. AC220 is a new selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML).

In vivo

In a xenograft tumor model, AC220 has nice drug attributes, good efficacy and high tolerability.. AC220 inhibits the activity of FLT3 and significantly extends survival in a mouse model of FLT3-ITD AML. Treatment with AC220 results in eradicating tumors in a xenograft tumor mouse model depended on FLT3. AC220 effectively inhibits the activity of FLT3 in primary cells of patients.

Features

Quizartinib (AC220) is a 2nd-generation FLT3 inhibitor as the first clinical drug candidate.

Description

Quizartinib (950769-58-1) is a potent and selective inhibitor of FLT3 (Kd?= 1.6nM, IC50?= 0.56 nM MV4-11 cells).1?It is in clinical trials for treatment of Acute Myelogenous Leukemia (AML).2,3?Quizartinib priming resulted in prevention of myelosuppression in mice treated with 5-FU and Gemcitabine.4?Quizartinib showed significant reversal of ABCG2-mediated multidrug resistance (@ 3 μM)?via?antagonism of drug efflux function.5,6

Uses

AC 220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML).

Definition

ChEBI: A member of the class of ureas that is urea in which one of the amino groups has been substituted by a 5-tert-butyl-1,2-oxazol-3-yl group while the other has been substituted by a phenyl group substituted at the para- position by n imidazo[2,1-b][1,3]benzothiazol-2-yl group that in turn is substituted at position 7 by a 2-(morpholin-4-yl)ethoxy group.

target

Flt3ITD

storage

Store at -20°C

References

1) Chao?et al.?(2009)?Identification of N-(5-tert-butyl-isoxazol-3-yl)-N’-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea dihydrochloride (AC220), a uniquely potent, selective, and efficacious FMS-like tyrosine kinase-3 (FLT3) inhibitor; J. Med. Chem.?52?7808 2) Zarrinkar?et al.?(2009);?AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia(AML); Blood?114?2984 3) Fathi and Chen (2017);?The role of FLT3 inhibitors in the treatment of FLT3-mutated acute myeloid leukemia; Eur. J .Haematol.?98?330 4) Taylor and Langdon (2017);?Hitting the snooze button: Inducing quiescence with the FLT3 inhibitor quizartinib protects hematopoietic progenitors from chemotherapy; Mol. Cell Oncol.?4?e1378156 5) Li?et al.?(2017);?Quizartinib (AC220) reverses ABCG2-mediated multidrug resistance: In vitro and In vivo studies; Oncotarget?8?93785 6) Bhullar?et al.?(2013)?The FLT3 inhibitor quizartinib inhibits ABCG2 at pharmacologically relevant concentrations, with implications for both chemosensitization and adverse drug reactions; PLoS One?8?e71266