Format

Send to

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

Pharmacologic inhibition of STAT5 in acute myeloid leukemia.

Author information

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.

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.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center