Pharmacologic inhibition of STAT5 in acute myeloid leukemia.

Leukemia
Bettina WingelhoferRichard Moriggl

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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Citations

Dec 6, 2018·Leukemia & Lymphoma·Xiaoxiao JiangXiucai Xu
Feb 19, 2019·Expert Opinion on Investigational Drugs·Joseph Cioccio, David Claxton
Apr 17, 2019·The Journal of Immunology : Official Journal of the American Association of Immunologists·Rashmi GuptaPatricia K A Mongini
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Jun 8, 2018·Molecular & Cellular Oncology·Ha Thi Thanh PhamRichard Moriggl
Jan 23, 2020·Cancers·Marie Brachet-BotineauFabrice Gouilleux
Nov 30, 2019·Organic & Biomolecular Chemistry·Robert A Cerulli, Joshua A Kritzer
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Jul 1, 2020·Trends in Molecular Medicine·Dirk Schmidt-Arras, Frank-D Böhmer
Aug 28, 2021·Biomedicines·Bernhard MoserDagmar Stoiber

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Methods Mentioned

BETA
thermal shift
nuclear magnetic resonance
Assay
RNA-seq
xenograft
NMR
acetylation

Software Mentioned

GSEA
GraphPad Prism

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