TY - JOUR
T1 - Discovery of 3-amide-pyrimidine-based derivatives as potential fms-like tyrosine receptor kinase 3 (FLT3) inhibitors for treating acute myelogenous leukemia
AU - Liu, Wei
AU - Ma, Yi
AU - Wang, Miaomiao
AU - He, Youyou
AU - Liu, Yanhong
AU - Zhu, Zhenbao
AU - Ding, Yi
AU - Zhang, Ge
AU - Wang, Shengzheng
N1 - Funding Information:
This work was supported by Natural Science Foundation of China (82373733), International Science and Technology Cooperation Program in Shaanxi Province (General Program) (Grant 2024GH-YBXM-18), Military Medicine Enhancement Program of FMMU (2021JSTS07).
Publisher Copyright:
© 2024 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.
PY - 2025/3/1
Y1 - 2025/3/1
N2 - 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.
AB - 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.
KW - Acute myelogenous leukemia
KW - Antitumor activity
KW - FLT3 inhibitor
KW - Structural optimization
UR - http://www.scopus.com/inward/record.url?scp=85212848148&partnerID=8YFLogxK
U2 - 10.1016/j.bmcl.2024.130082
DO - 10.1016/j.bmcl.2024.130082
M3 - Journal article
AN - SCOPUS:85212848148
SN - 0960-894X
VL - 117
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
M1 - 130082
ER -
