Description
Quizartinib is an oral and potent fms-like tyrosine kinase 3 (FLT3) inhibitor and it is the first drug developed specifically targeting FLT3, as other agents with FLT3 inhibition activities were investigated with other targets in mind. Additionally, quizartinib also demonstrates inhibitory activity toward FLT3 with internal tandem duplication (ITD), although with a 10-fold lower affinity compared to wild-type FLT3. FLT3-ITD mutation is present in 75% of FLT3-mutated AML, leading to constitutively active FLT3 and thus poorer overall survival and higher risk of relapse. Multiple clinical trials have demonstrated quizartinib's efficacy in relapsed/refractory FLT3-ITD mutant AML. Therefore, quizartinib is proven to be a beneficial addition to the current AML treatment regimen, although serious side effects such as QT prolongation necessitates further research to optimize quizartinib's addition to AML standard of care. Quizartinib was approved by the FDA in July 2023 and developed under the brand name VANFLYTA by Daiichi Sankyo. The FDA approval was based on positive results from the QuANTUM-First trial for FLT3-ITD positive AML, where quizartinib combined with standard cytarabine and anthracycline induction and standard cytarabine consolidation, followed by a maintenance monotherapy resulted in a 22% reduction in the risk of death.
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 is an oral, highly potent, and selective next-generation FLT3 inhibitor (Kd= 1.6nM, IC50= 0.56 nM MV4-11 cells) with clinical antileukaemic activity in relapsed or refractory acute myeloid leukaemia. Quizartinib priming resulted in prevention of myelosuppression in mice treated with 5-FU and Gemcitabine. Quizartinib showed significant reversal of ABCG2-mediated multidrug resistance (@ 3 μM) via antagonism of drug efflux function.?
Uses
AC 220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML).
Definition
ChEBI: Quizartinib is a member of the class of phenylureas 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 an 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. It has a role as an EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor, an antineoplastic agent and a necroptosis inhibitor. It is a benzoimidazothiazole, a member of morpholines, a member of isoxazoles and a member of phenylureas.
References
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10.1021/jm9007533.
[2] PATRICK P ZARRINKAR. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML).[J]. ACS Nano, 2009: 2984-2992. DOI:
10.1182/blood-2009-05-222034.
[3] AMIR T. FATHI Yi B C. The role of FLT3 inhibitors in the treatment of FLT3-mutated acute myeloid leukemia[J]. European Journal of Haematology, 2016, 98 4: 330-336. DOI:
10.1111/ejh.12841.
[4] SAMUEL J TAYLOR Wallace Y L. Hitting the snooze button: Inducing quiescence with the FLT3 inhibitor quizartinib protects hematopoietic progenitors from chemotherapy.[J]. Molecular and Cellular Oncology, 2017, 4 6: e1378156. DOI:
10.1080/23723556.2017.1378156.
[5] JUN LI. Quizartinib (AC220) reverses ABCG2-mediated multidrug resistance: In vitro and in vivo studies.[J]. Oncotarget, 2017: 93785-93799. DOI:
10.18632/oncotarget.21078.
[6] JASJEET BHULLAR. The FLT3 inhibitor quizartinib inhibits ABCG2 at pharmacologically relevant concentrations, with implications for both chemosensitization and adverse drug interactions.[J]. ACS Applied Bio Materials, 2013: e71266. DOI:
10.1371/journal.pone.0071266.
[7] JORGE CORTES. Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial.[J]. Journal of Agricultural and Food Chemistry, 2018: 889-903. DOI:
10.1016/S1470-2045(18)30240-7.
