Signal transducer and activator of transcription 5 (STAT5) is a member of the STAT protein family. It is relevant to cell growth and differentiation. Specifically, STAT5 protein has related to cytoplasmic signal transduction and mediates the expression of specific genes. Abnormal STAT5 activity is closely related to a variety of human cancers. Besides, the Src homology 2 (SH2) domain appears in the metazoan signaling pathway. Moreover, it is involved in the protein regulation of multiple pleiotropic cascades. In STAT proteins, SH2 domain interaction is crucial for the molecular activation and nuclear accumulation of phosphorylated stat dimers to drive transcription. Normal stat function depends on the SH2 domain. Furthermore, this domain determines homogeneous or heterogeneous stat dimerization and multiple protein-protein interactions. Therefore, the structurally altered SH2 domain has a considerable effect on stat activity.

Meanwhile, STAT5 is a key member of the JAK/STAT core cancer pathway. The transcription factor STAT5 is an important downstream mediator of many tyrosine kinases (TKS), especially in hematopoietic cancers. Nonetheless, STAT5 is activated by FLT3-itd, a constitutively active TK that drives the pathogenesis of acute myeloid leukemia (AML). Additionally, High pY-STAT5 levels are negative prognostic markers of myeloid malignancies. Here, we will introduce a potent STAT5 SH2 domain inhibitor, AC-4-130.

AC-4-130 is a Potent STAT5 SH2 Domain Inhibitor.

To begin with, AC-4-130 directly binds to STAT5 and disrupts STAT5 activation, dimerization, nuclear translocation, and STAT5-dependent gene transcription. Interestingly, AC-4-130 induces cell cycle arrest and apoptosis in FLT3-ITD-driven leukemic cells. Importantly, AC-4-130 has anti-cancer activity and can efficiently block pathological levels of STAT5 activity in AML.

Secondly, AC-4-130 with 0.1-100 µM for 72 hours leads to apoptosis in a dose-dependent and time-dependent manner in MV4-11 or MOLM-13 cells. Particularly, AC-4-130 induces cell cycle arrest with an increase in G0/G1 arrested cells. Obviously, AC-4-130 induces a concomitant reduction in cells in S or G2/M. AC-4-130 reveals reduced pY-STAT5 levels both in the cytoplasm and nucleus. By the way, AC-4-130-mediated STAT5 inhibition efficiently blocks the proliferation and clonogenic growth of primary human AML cells. While healthy CD34+ cells are less sensitive.

All in all, AC-4-130 is a potent STAT5 SH2 domain inhibitor.


Bettina Wingelhofer, et al. Leukemia. 2018 May;32(5):1135-1146.