2. Academic Validation
  3. Design, synthesis, and Lead optimization of novel Quinazoline-based FLT3 inhibitors with potent anti-acute myelogenous leukemia activity

Design, synthesis, and Lead optimization of novel Quinazoline-based FLT3 inhibitors with potent anti-acute myelogenous leukemia activity

  • Bioorg Med Chem Lett. 2026 Mar 3:136:130608. doi: 10.1016/j.bmcl.2026.130608.
Wei Liu 1,  Shuaibo Du 2,  Miaomiao Wang 2,  Shuhan Sun 2,  Lei Wang 2,  Jin Liu 3,  Shengzheng Wang 4
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 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: [email protected].
  • 4 Department of Medicinal Chemistry and Pharmaceutical Analysis, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi 710032, China. Electronic address: [email protected].
PMID: 41786054 DOI: 10.1016/j.bmcl.2026.130608
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.

Keywords

Antitumor activity; FLT3 inhibitor; Quinazoline derivatives; Structure optimization.

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