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Oncotarget | Quizartinib, a selective FLT3 inhibitor, maintains antileukemic activity in preclinical models of RAS-mediated midostaurin-resistant acute myeloid leukemia cells


Oncotarget Volume 11, Issue 11 reported that in this preclinical study, we characterized the binding affinity and selectivity of quizartinib, a small-molecule inhibitor of FLT3, and AC886, the active metabolite of quizartinib, compared with those of other FLT3 inhibitors.

Dr. Takeshi Isoyama from Daiichi Sankyo Co., Ltd. said, "FMS like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase expressed by acute myeloid leukemia (AML) cells in 70% to 90% of patients."

"FMS like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase expressed by acute myeloid leukemia (AML) cells in 70% to 90% of patients."

- Dr. Takeshi Isoyama, Daiichi Sankyo Co., Ltd

FLT3 mutations have been found in approximately 30% of AML cases, with internal tandem duplication, commonly found in the juxtamembrane domain of FLT3, occurring in approximately 25% of cases and mutations in the tyrosine kinase domain present in approximately 5%.

Generally, type II inhibitors are more selective than type I inhibitors, as the inactive conformation preferred by type II inhibitors is thought to be more kinase-specific than the active conformation.

Secondary kinase mutations can emerge in FLT3-ITD AML, resulting in resistance to FLT3 inhibitors, and point mutations that confer resistance to a certain FLT3 inhibitor tend to have cross-resistance to other drugs in the same class.

Figure 1: Chemical structure and kinase selectivity profiling of quizartinib, AC886, and other FLT3 inhibitors. (A) Chemical structures of midostaurin, gilteritinib, crenolanib, quizartinib, AC886, and sorafenib. (B) Binding affinity of compounds was measured against 404 nonmutant kinases. Kd values were calculated from duplicate 11-point dose-response curves. Each red circle represents a kinase bound to each compound. Larger circles indicate higher binding affinity of each compound to kinases. Kinases with Kd values <3000 nM are shown. Blue circles represent FLT3.

Limited data exist on the efficacy of available FLT3 inhibitors in patients with AML that was relapsed or refractory to first-line midostaurin-based therapy, and strategies to overcome resistance mutations, such as a combination of inhibitors or use of more potent FLT3 inhibitors, are being evaluated.

The objectives of this preclinical study were to characterize the kinase binding affinity and selectivity of quizartinib and its active metabolite AC886 compared with those of other FLT3 inhibitors, to evaluate the antitumor effect of quizartinib on midostaurin-resistant AML cells, and to assess the impact of midostaurin resistance on FLT3 inhibitors.

The Isoyama Research Team concluded in their Oncotarget Research Paper, "we have demonstrated the high affinity and selectivity that quizartinib and its active metabolite AC886 have for FLT3 and that quizartinib maintains preclinical antitumor activity against midostaurin-resistant tumor models. Additional clinical trials will be needed to clarify and optimize the role of quizartinib in the treatment of patients with relapsed or refractory AML who have previously been treated with midostaurin."

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DOI - https://doi.org/10.18632/oncotarget.27489

Full text - https://www.oncotarget.com/article/27489/text/

Correspondence to - Takeshi Isoyama - isoyama.takeshi.y5@daiichisankyo.co.jp

Keywords - relapsed/refractory AML, FLT3 inhibitors, quizartinib, AC886, midostaurin resistance

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