IRAK1/4/pan-FLT3 Kinase Inhibitors with Reduced hERG Block as Treatments for Acute Myeloid Leukemia

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-04-29 DOI:10.1021/acsmedchemlett.5c0014710.1021/acsmedchemlett.5c00147

Scott B. Hoyt*, Chris J. Finocchio, Elizabeth Croll, Gregory J. Tawa, Mingliang Zhang, Jiangong Wang, Huixi Li, Li Ma, Kaikai Li, Xiaohu Zhang, Xin Xu, Pranav Shah, 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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引用次数: 0

Abstract

We report the optimization of a series of IRAK1/4/pan-FLT3 kinase inhibitors. These efforts have produced a key compound 27 that displays potent and selective inhibition of IRAK1, IRAK4, and FLT3, reduced block of hERG, and good pharmacokinetic properties. In a mouse xenograft model of acute myeloid leukemia (AML), 27 produces survival prolongation superior to that of gilteritinib, the leading FDA-approved FLT3 inhibitor currently used to treat AML.

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IRAK1/4/pan-FLT3激酶抑制剂减少hERG阻滞治疗急性髓性白血病

我们报道了一系列IRAK1/4/pan-FLT3激酶抑制剂的优化。这些努力已经产生了一种关键化合物27，它显示出对IRAK1、IRAK4和FLT3的有效和选择性抑制，减少了hERG的阻断，并具有良好的药代动力学特性。在急性髓性白血病（AML）的小鼠异种移植模型中，27的生存期延长优于吉尔替尼（gilteritinib），后者是fda批准的FLT3抑制剂，目前用于治疗AML。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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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.