Liu Wei, Ma Yi, Wang Miaomiao, He Youyou, Liu Yanhong, Zhu Zhenbao, Ding Yi, Zhang Ge, Wang Shengzheng
Faculty of Pharmacy, School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi'an, Shaanxi 710021, China; Department of Medicinal Chemistry and Pharmaceutical Analysis, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
Faculty of Pharmacy, School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi'an, Shaanxi 710021, China.
Bioorg Med Chem Lett. 2025 Mar 1;117:130082. doi: 10.1016/j.bmcl.2024.130082. Epub 2024 Dec 19.
FLT3-ITD and TKD mutants play a central role in acute myeloid leukemia (AML), making FLT3 an attractive target for AML treatment. To discover next-generation FLT3 inhibitors and gather additional structure-activity relationship (SAR) information, we performed structural modifications of G-749 (denfivontinib) utilizing structure simplification and scaffold hopping strategies. Among these derivatives, MY-10 exhibited the most potent and selective inhibition of MV4-11 cell proliferation, demonstrating potent inhibitory activity against FLT3-ITD (IC = 6.5 nM) and FLT3-D835Y (IC = 10.3 nM) mutants. Notably, MY-10 exhibited no inhibitory activity against c-KIT kinase (IC > 100 μM). Mechanistic studies revealed that MY-10 arrested the cell cycle at the G0/G1 phase and efficiently induced apoptosis. Furthermore, it significantly reduced reactive oxygen species (ROS) production and mitochondrial membrane potential (MMP), and strongly inhibited FLT3-mediated signaling pathways. These findings, along with the obtained SAR information, provide valuable insights for the further development of FLT3 inhibitors.
FLT3内部串联重复（FLT3-ITD）和酪氨酸激酶结构域（TKD）突变体在急性髓系白血病（AML）中起核心作用，这使得FLT3成为AML治疗的一个有吸引力的靶点。为了发现下一代FLT3抑制剂并收集更多的构效关系（SAR）信息，我们利用结构简化和骨架跃迁策略对G-749（登菲凡替尼）进行了结构修饰。在这些衍生物中，MY-10对MV4-11细胞增殖表现出最有效和选择性的抑制作用，对FLT3-ITD（IC = 6.5 nM）和FLT3-D835Y（IC = 10.3 nM）突变体表现出强效抑制活性。值得注意的是，MY-10对c-KIT激酶没有抑制活性（IC > 100 μM）。机制研究表明，MY-10使细胞周期停滞在G0/G1期并有效诱导凋亡。此外，它显著降低活性氧（ROS）的产生和线粒体膜电位（MMP），并强烈抑制FLT3介导的信号通路。这些发现以及获得的SAR信息为FLT3抑制剂的进一步开发提供了有价值的见解。
