2. Academic Validation
  3. Pharmacologic inhibition of STAT5 in acute myeloid leukemia

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

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. richard.moriggl@lbicr.lbg.ac.at.
  • 10 Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria. richard.moriggl@lbicr.lbg.ac.at.
  • 11 Medical University of Vienna, Vienna, Austria. richard.moriggl@lbicr.lbg.ac.at.
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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