Design, Synthesis, and Biological Activities Evaluation of Type I FLT3 Inhibitors for the Treatment of Acute Myeloid Leukemia

Drug Dev Res. 2024 Dec;85(8):e70022. doi: 10.1002/ddr.70022.

Abstract

The abnormal overexpression of FLT3 kinase is intimately associated with pathogenesis of acute myeloid leukemia (AML), positioning FLT3 inhibitors as pivotal therapeutic agents. Despite the availability of three FDA-approved FLT3 inhibitors, their clinical utility is hampered by resistance stemming from tyrosine kinase domain (TKD) mutations. Through an integrative analysis of case studies, we identified a potential advantage of type I FLT3 inhibitors in overcoming TKD mutation-induced resistance. Structure-activity relationships (SAR) analysis indicated that FW-1 exhibited over 50% inhibition against FLT3 at a concentration of 1 μM and demonstrated potent activity against AML cell lines MV4-11 (IC50 = 2.68 μM) and MOLM-13 (IC50 = 1.03 μM). In our cellular mechanistic studies, FW-1 also effectively induced apoptosis by arresting cell cycle progression in the G0/G1 phase. This study introduces FW-1 as a promising lead for type I FLT3 inhibitor, warranting further optimization.

MeSH terms

  • Antineoplastic Agents* / chemical synthesis
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Apoptosis* / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Design*
  • Humans
  • Leukemia, Myeloid, Acute* / drug therapy
  • Protein Kinase Inhibitors* / chemical synthesis
  • Protein Kinase Inhibitors* / chemistry
  • Protein Kinase Inhibitors* / pharmacology
  • Structure-Activity Relationship
  • fms-Like Tyrosine Kinase 3* / antagonists & inhibitors

Substances

  • fms-Like Tyrosine Kinase 3
  • FLT3 protein, human
  • Protein Kinase Inhibitors
  • Antineoplastic Agents