Pharmacologic inhibition of STAT5 in acute myeloid leukemia

Leukemia. 2018 May;32(5):1135-1146. doi: 10.1038/s41375-017-0005-9. Epub 2018 Feb 2.


The transcription factor STAT5 is an essential downstream mediator of many tyrosine kinases (TKs), particularly in hematopoietic cancers. STAT5 is activated by FLT3-ITD, which is a constitutively active TK driving the pathogenesis of acute myeloid leukemia (AML). Since STAT5 is a critical mediator of diverse malignant properties of AML cells, direct targeting of STAT5 is of significant clinical value. Here, we describe the development and preclinical evaluation of a novel, potent STAT5 SH2 domain inhibitor, AC-4-130, which can efficiently block pathological levels of STAT5 activity in AML. AC-4-130 directly binds to STAT5 and disrupts STAT5 activation, dimerization, nuclear translocation, and STAT5-dependent gene transcription. Notably, AC-4-130 substantially impaired the proliferation and clonogenic growth of human AML cell lines and primary FLT3-ITD+ AML patient cells in vitro and in vivo. Furthermore, AC-4-130 synergistically increased the cytotoxicity of the JAK1/2 inhibitor Ruxolitinib and the p300/pCAF inhibitor Garcinol. Overall, the synergistic effects of AC-4-130 with TK inhibitors (TKIs) as well as emerging treatment strategies provide new therapeutic opportunities for leukemia and potentially other cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Synergism
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / genetics
  • Nitriles
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Pyrazoles / pharmacology
  • Pyrimidines
  • STAT5 Transcription Factor / antagonists & inhibitors*
  • Terpenes / pharmacology
  • fms-Like Tyrosine Kinase 3


  • Nitriles
  • Pyrazoles
  • Pyrimidines
  • STAT5 Transcription Factor
  • Terpenes
  • ruxolitinib
  • Protein-Tyrosine Kinases
  • fms-Like Tyrosine Kinase 3
  • garcinol