Aminoisoquinoline benzamides, FLT3 and Src-family kinase inhibitors, potently inhibit proliferation of acute myeloid leukemia cell lines

Future Med Chem. 2017 Jul;9(11):1213-1225. doi: 10.4155/fmc-2017-0067. Epub 2017 May 11.


Aim: Mutated or overexpressed FLT3 drives about 30% of reported acute myeloid leukemia (AML). Currently, FLT3 inhibitors have shown durable clinical responses but a complete remission of AML with FLT3 inhibitors remains elusive due to mutation-driven resistance mechanisms. The development of FLT3 inhibitors that also target other downstream oncogenic kinases may combat the resistance mechanism.

Results: 4-substituted aminoisoquinoline benzamides potently inhibit Src-family kinases and FLT3, including secondary mutations, such as FLT3D835. Modifications of aminoisoquinoline benzamide to aminoquinoline or aminoquinazoline abrogated FLT3 and Src-family kinase binding.

Conclusion: The lead aminoisoquinolines potently inhibited FLT3-driven AML cell lines, MV4-11 and MOLM-14. These aminoisoquinoline benzamides represent new kinase scaffolds with high potential to be translated into anticancer agents.

Keywords: FLT3; MOLM-14; MV4–11; SRC-family kinase; acute myeloid leukemia; multikinase inhibitor; receptor tyrosine kinase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Apoptosis
  • Benzamides / chemical synthesis*
  • Benzamides / pharmacology
  • Binding Sites
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Humans
  • Isoquinolines / chemical synthesis*
  • Isoquinolines / pharmacology
  • Leukemia, Myeloid, Acute / drug therapy*
  • Molecular Docking Simulation
  • Mutation
  • Protein Binding
  • Protein Conformation
  • fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*
  • src-Family Kinases / antagonists & inhibitors*


  • Antineoplastic Agents
  • Benzamides
  • Isoquinolines
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3
  • src-Family Kinases