2. Academic Validation
  3. Discovery of 3-amide-pyrimidine-based derivatives as potential fms-like tyrosine receptor kinase 3 (FLT3) inhibitors for treating acute myelogenous leukemia

Discovery of 3-amide-pyrimidine-based derivatives as potential fms-like tyrosine receptor kinase 3 (FLT3) inhibitors for treating acute myelogenous leukemia

  • Bioorg Med Chem Lett. 2025 Mar 1:117:130082. doi: 10.1016/j.bmcl.2024.130082.
Wei Liu 1,  Yi Ma 2,  Miaomiao Wang 2,  Youyou He 2,  Yanhong Liu 2,  Zhenbao Zhu 2,  Yi Ding 3,  Ge Zhang 4,  Shengzheng Wang 5
Affiliations

Affiliations

  • 1 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.
  • 2 Faculty of Pharmacy, School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi'an, Shaanxi 710021, China.
  • 3 Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi' an, Shaanxi 710021, China. Electronic address: dingyi.007@163.com.
  • 4 Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases (TMBJ), School of Chinese Medicine, Hong Kong Baptist University (HKBU), Hong Kong Special Administrative Region. Electronic address: zhangge@hkbu.edu.hk.
  • 5 Department of Medicinal Chemistry and Pharmaceutical Analysis, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi 710032, China. Electronic address: wangshengzheng001@163.com.
PMID: 39708925 DOI: 10.1016/j.bmcl.2024.130082
Abstract

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 (IC50 = 6.5 nM) and FLT3-D835Y (IC50 = 10.3 nM) mutants. Notably, MY-10 exhibited no inhibitory activity against c-Kit kinase (IC50 > 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.

Keywords

Acute myelogenous leukemia; Antitumor activity; FLT3 inhibitor; Structural optimization.

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