发现 IRAK1/4/泛 FLT3 激酶抑制剂可用于治疗急性髓系白血病。
Discovery of IRAK1/4/pan-FLT3 Kinase Inhibitors as Treatments for Acute Myeloid Leukemia.
作者信息
Hoyt Scott B, Finocchio Chris J, Croll Elizabeth, Tawa Gregory J, Li Huixu, Ma Li, Li Kaikai, Liu Li, Li Ranran, Zhang Xiaohu, Wilson Kelli, Xu Xin, Shah Pranav, Williams Jordan, Fang Yuhong, Bolanos Lyndsey C, Gracia-Maldonado Gabriel, Kolt Amal, Robinson Christina, Free Jessica, Edmondson Elijah F, Difilippantonio Simone, Jones LaQuita M, Culver-Cochran Ashley E, Rosenbaum Jan S, Starczynowski Daniel T, Thomas Craig J
机构信息
National Center for Advancing Translational Sciences, Rockville, Maryland 20850, United States.
WuXi AppTec Co. Ltd., 168 Nanhai Road, TEDA, Tianjin 300457, People's Republic of China.
出版信息
ACS Med Chem Lett. 2024 Oct 23;15(11):1843-1851. doi: 10.1021/acsmedchemlett.4c00269. eCollection 2024 Nov 14.
We report the discovery of an imidazopyridine series of IRAK1/4/pan-FLT3 kinase inhibitors. Optimization of this series has produced compound 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, produces survival prolongation equal to that of Gilteritinib, the leading marketed FLT3 inhibitor currently used to treat AML.
我们报告了一种咪唑并吡啶系列的IRAK1/4/泛FLT3激酶抑制剂的发现。对该系列进行优化得到了化合物，它对IRAK1、IRAK4、FLT3以及FLT3的所有突变形式均表现出强效且选择性的抑制作用，同时还具有良好的体外吸收、分布、代谢和排泄（ADME）及药代动力学性质。在急性髓系白血病（AML）的小鼠异种移植模型中，该化合物使生存期延长的程度与目前用于治疗AML的市售领先FLT3抑制剂吉列替尼相当。
Zotero 插件