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Pharmacologic Inhibition of STAT5 in Acute Myeloid Leukemia

Pharmacologic Inhibition of STAT5 in Acute Myeloid Leukemia

Bettina Wingelhofer, Barbara Maurer, Elizabeth C Heyes, Abbarna A Cumaraswamy, Angelika Berger-Becvar, Elvin D de Araujo, Anna Orlova, Patricia Freund, Frank Ruge, Jisung Park, Gary Tin, Siawash Ahmar, etc.

Leukemia. 2018 May;32(5):1135-1146.

PMID: 29472718

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42411959	Flt3 active human			Price
IAR42416387	Jak1 active human			Price

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