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

作者：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 Bolanos, Gabriel Gracia-Maldonado, Amal Kolt, Christina M. Robinson, Jessica Free, Elijah F. Edmondson, Simone Difilippantonio, LaQuita M. Jones, Ashley E. Culver‐Cochran, Jan S. Rosenbaum, Daniel T. Starczynowski, Craig J. Thomas · 发表于：ACS Medicinal Chemistry Letters · 年份：2025 · DOI：10.1021/acsmedchemlett.5c00147 · 被引用次数：6 · 研究领域：Acute Myeloid Leukemia Research、Protein Degradation and Inhibitors、Histone Deacetylase Inhibitors Research

High Resolution Image Download MS PowerPoint Slide 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.