Design and Synthesis of New Sulfonamides-Based Flt3 Inhibitors

Med Chem. 2020;16(3):403-412. doi: 10.2174/1573406415666190401144053.

Abstract

Background: Flt3 is an oncogenic kinase involved in different leukemias. It is most prominently associated with acute myeloid leukemia (AML). Flt3-specific inhibitors have shown promising results in interfering with AML.

Methods: The crystallographic structures of two inhibitors complexed within Flt3, namely, quizartinib and F6M, were used to guide the synthesis of new sulfonamide-based Flt3 inhibitors.

Results: One of the prepared compounds showed low micromolar anti-Flt3 bioactivity, and interestingly, low micromolar bioactivity against the related oncogenic kinase VEGFR2.

Conclusion: Sulfonamides were successfully used as privileged scaffolds for the synthesis of novel Flt3 inhibitors of micromolar potencies.

Keywords: Acute Myeloid Leukemia; F6M; Flt3; Quizatrinib; Sulfonamides; VEGFR2..

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Drug Design
  • Drug Screening Assays, Antitumor
  • Humans
  • Molecular Docking Simulation
  • Protein Binding
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Sulfonamides / chemical synthesis
  • Sulfonamides / metabolism
  • Sulfonamides / pharmacology*
  • fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*
  • fms-Like Tyrosine Kinase 3 / metabolism

Substances

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