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Updated: Mar 7, 2026
Comet Assay to Quantify DNA Damage in FLT3 Mutant-expressing 32D Cells after Exposure to Type I and Type II FLT3 Inhibitors
Published on: October 17, 2025
Design, synthesis, and Lead optimization of novel Quinazoline-based FLT3 inhibitors with potent anti-acute
Wei Liu1, Shuaibo Du2, Miaomiao Wang2
1Faculty 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.
Abstract:
FLT3 mutations, including internal tandem duplications (ITD) and tyrosine kinase domain (TKD) variants, are key drivers of acute myeloid leukemia (AML) and represent attractive therapeutic targets. Guided by a scaffold-hopping strategy based on G-749 (denfivontinib), a series of quinazoline-based derivatives was designed and synthesized to explore structure-activity relationships (SAR). Among them, compound W4 showed the most promising profile, exhibiting potent antiproliferative activity against MV4-11 and MOLM-13 cells and strong inhibition of FLT3-ITD (IC50 = 16.0 nM) and FLT3-D835Y (IC50 = 20.4 nM), while displaying negligible activity toward c-KIT kinase (IC50 > 100 μM). Mechanism studies indicated that W4 induced G0/G1 cell cycle arrest and apoptosis, accompanied by a reduction in intracellular reactive oxygen species levels and a loss of mitochondrial membrane potential. Collectively, these results identified W4 as a potent FLT3 inhibitor and provided valuable SAR insights for further scaffold optimization.
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