Discovery of IRAK1/4/pan-FLT3 Kinase Inhibitors as Treatments for Acute Myeloid Leukemia

被引：1

作者：

Hoyt, Scott B. ^{[1
]}

Finocchio, Chris J. ^{[1
]}

Croll, Elizabeth ^{[1
]}

Tawa, Gregory J. ^{[1
]}

Li, Huixu ^{[2
]}

Ma, Li ^{[2
]}

Li, Kaikai ^{[2
]}

Liu, Li ^{[2
]}

Li, Ranran ^{[2
]}

Zhang, Xiaohu ^{[1
]}

Wilson, Kelli ^{[1
]}

Xu, Xin ^{[1
]}

Shah, Pranav ^{[1
]}

Williams, Jordan ^{[1
]}

Fang, Yuhong ^{[1
]}

Bolanos, Lyndsey C. ^{[3
]}

Gracia-Maldonado, Gabriel ^{[4
]}

Kolt, Amal ^{[4
]}

Robinson, Christina ^{[5
]}

Free, Jessica ^{[5
]}

Edmondson, Elijah F. ^{[5
]}

Difilippantonio, Simone ^{[5
]}

Jones, LaQuita M. ^{[6
]}

Culver-Cochran, Ashley E. ^{[3
]}

Rosenbaum, Jan S. ^{[4
]}

Starczynowski, Daniel T. ^{[3
]}

Thomas, Craig J. ^{[1
,7
]}

机构：

[1] Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA

[2] WuXi AppTec Co Ltd, Tianjin 300457, Peoples R China

[3] Cincinnati Childrens Hosp Med Ctr, Div Expt Hematol, Cincinnati, OH 45229 USA

[4] Kurome Therapeut, Cincinnati, OH 45208 USA

[5] Frederick Natl Lab Canc Res, Frederick, MD 21702 USA

[6] Cincinnati Childrens Hosp Med Ctr, Div Oncol, Cincinnati, OH 45229 USA

[7] NCI, Bethesda, MD 20814 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2024年 / 15卷 / 11期

基金：

美国国家卫生研究院;

关键词：

IRAK1; IRAK4; FLT3; kinase; AML; leukemia;

D O I：

10.1021/acsmedchemlett.4c00269

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We report the discovery of an imidazopyridine series of IRAK1/4/pan-FLT3 kinase inhibitors. Optimization of this series has produced compound 31 which displays potent and selective inhibition of IRAK1, IRAK4, FLT3, and all mutant forms of FLT3, as well as good in vitro ADME and pharmacokinetic properties. In a mouse xenograft model of AML, 31 produces survival prolongation equal to that of Gilteritinib, the leading marketed FLT3 inhibitor currently used to treat AML.

引用

页码：1843 / 1851

页数：9

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