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

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-10-23 DOI:10.1021/acsmedchemlett.4c0026910.1021/acsmedchemlett.4c00269

Scott B. Hoyt*, Chris J. Finocchio, Elizabeth Croll, Gregory J. Tawa, Huixu Li, Li Ma, Kaikai Li, Li Liu, Ranran Li, Xiaohu Zhang, Kelli Wilson, Xin Xu, Pranav Shah, Jordan Williams, Yuhong Fang, Lyndsey C. Bolanos, Gabriel Gracia-Maldonado, Amal Kolt, Christina Robinson, Jessica Free, Elijah F. Edmondson, Simone Difilippantonio, LaQuita M. Jones, Ashley E. Culver-Cochran, Jan S. Rosenbaum, Daniel T. Starczynowski and Craig J. Thomas,

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Abstract

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.

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发现可治疗急性髓性白血病的 IRAK1/4/pan-FLT3 激酶抑制剂

我们报告了IRAK1/4/pan-FLT3激酶抑制剂咪唑吡啶系列的发现。对该系列进行优化后，化合物 31 对 IRAK1、IRAK4、FLT3 和 FLT3 的所有突变形式都具有强效的选择性抑制作用，同时还具有良好的体外 ADME 和药代动力学特性。在急性髓细胞性白血病小鼠异种移植模型中，31 能延长患者的存活时间，与目前用于治疗急性髓细胞性白血病的主要上市 FLT3 抑制剂 Gilteritinib 的效果相当。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.

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