Macrocyclic compounds as anti-cancer agents: design and synthesis of multi-acting inhibitors against HDAC, FLT3 and JAK2

Eur J Med Chem. 2015 May 5:95:104-15. doi: 10.1016/j.ejmech.2015.03.034. Epub 2015 Mar 17.

Abstract

A novel series of macrocyclic compounds were designed and synthesized as multi-target inhibitors targeting HDAC, FLT3 and JAK2. Some of these compounds exhibited potent HDAC inhibition as well as FLT3 and JAK2 inhibition under both cell-free and cellular conditions. In vitro antiproliferative assay indicated that these compounds were interestingly more cytotoxic to MV4-11 cells bearing FLT3-ITD mutation and HEL cells bearing JAK2(V617F) mutation.

Keywords: FLT3; Histone deacetylase; JAK2; Macrocyclic; Multi-target inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Blotting, Western
  • Cell Proliferation / drug effects
  • Drug Design*
  • HeLa Cells
  • Histone Deacetylase Inhibitors / chemical synthesis
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Deacetylases / chemistry*
  • Humans
  • Janus Kinase 2 / antagonists & inhibitors*
  • Macrocyclic Compounds / chemical synthesis*
  • Macrocyclic Compounds / pharmacology*
  • Molecular Docking Simulation
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / pharmacology
  • Signal Transduction
  • fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*

Substances

  • Antineoplastic Agents
  • Histone Deacetylase Inhibitors
  • Macrocyclic Compounds
  • Protein Kinase Inhibitors
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3
  • JAK2 protein, human
  • Janus Kinase 2
  • Histone Deacetylases