Pharmacologic inhibition of STAT5 in acute myeloid leukemia

  • Leukemia. 2018 May;32(5):1135-1146. doi: 10.1038/s41375-017-0005-9.
Bettina Wingelhofer  1  2 ,  Barbara Maurer  3 ,  Elizabeth C Heyes  1 ,  Abbarna A Cumaraswamy  4  5 ,  Angelika Berger-Becvar  4  5 ,  Elvin D de Araujo  4  5 ,  Anna Orlova  1  2 ,  Patricia Freund  1  2 ,  Frank Ruge  1  2 ,  Jisung Park  4  5 ,  Gary Tin  4  5 ,  Siawash Ahmar  4  5 ,  Charles-Hugues Lardeau  6 ,  Irina Sadovnik  7 ,  Dávid Bajusz  8 ,  György Miklós Keserű  8 ,  Florian Grebien  1 ,  Stefan Kubicek  6 ,  Peter Valent  7 ,  Patrick T Gunning  4  5 ,  Richard Moriggl  9  10  11
Affiliations
  • 1. Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
  • 2. Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.
  • 3. Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria.
  • 4. Department of Chemical & Physical Sciences, University of Toronto Mississauga, Mississauga, ON, Canada.
  • 5. Department of Chemistry, University of Toronto, Toronto, ON, Canada.
  • 6. Research Center for Molecular Medicine (CeMM), Vienna, Austria.
  • 7. Department of Internal Medicine I, Division of Hematology & Hemostaseology, Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.
  • 8. Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
  • 9. Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria. [email protected].
  • 10. Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria. [email protected].
  • 11. Medical University of Vienna, Vienna, Austria. [email protected].
PMID: 29472718 DOI: 10.1038/s41375-017-0005-9
Abstract

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.

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