Targeting AML-associated FLT3 mutations with a type I kinase inhibitor

被引：31

作者：

Jones, LaQuita M. ^{[1
]}

Melgar, Katelyn ^{[2
,3
]}

Bolanos, Lyndsey ^{[2
]}

Hueneman, Kathleen ^{[2
]}

Walker, Morgan M. ^{[4
]}

Jiang, Jian-Kang ^{[4
]}

Wilson, Kelli M. ^{[4
]}

Zhang, Xiaohu ^{[4
]}

Shen, Jian ^{[5
]}

Jiang, Fan ^{[5
]}

Sutter, Patrick ^{[4
]}

Wang, Amy ^{[4
]}

Xu, Xin ^{[4
]}

Tawa, Gregory J. ^{[4
]}

Hoyt, Scott B. ^{[4
]}

Wunderlich, Mark ^{[2
]}

O'Brien, Eric ^{[1
]}

Perentesis, John P. ^{[1
]}

Starczynowski, Daniel T. ^{[2
,6
]}

Thomas, Craig J. ^{[4
,7
]}

机构：

[1] Cincinnati Childrens Hosp Med Ctr, Canc & Blood Dis Inst, Div Oncol, Cincinnati, OH 45229 USA

[2] Cincinnati Childrens Hosp Med Ctr, Canc & Blood Dis Inst, Div Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA

[3] Univ Cincinnati, Coll Med, Immunol Grad Program, Cincinnati, OH USA

[4] NIH, Div Preclin Innovat, Natl Ctr Advancing Translat Sci, Bldg 10, Bethesda, MD 20892 USA

[5] Viva Biotech Ltd, Shanghai, Peoples R China

[6] Univ Cincinnati, Coll Med, Dept Canc Biol, Cincinnati, OH USA

[7] NCI, Lymphoid Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2020年 / 130卷 / 04期

关键词：

ACUTE MYELOID-LEUKEMIA; RESISTANCE; QUIZARTINIB;

D O I：

10.1172/JCI127907

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Tyrosine kinase domain (TKD) mutations contribute to acquired resistance to FMS-like tyrosine kinase 3 (FLT3) inhibitors used to treat FLT3-mutant acute myeloid leukemia (AML). We report a cocrystal structure of FLT3 with a type I inhibitor, NCGC1481, that retained potent binding and activity against FLT3 TKD and gatekeeper mutations. Relative to the current generation of advanced FLT3 inhibitors, NCGC1481 exhibited superior antileukemic activity against the common, clinically relevant FLT3-mutant AML cells in vitro and in vivo.

引用

页码：2017 / 2023

页数：7

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