1 research outputs found
Small Molecule STAT5-SH2 Domain Inhibitors Exhibit Potent Antileukemia Activity
A growing body of evidence shows that Signal Transducer
and Activator
of Transcription 5 (STAT5) protein, a key member of the STAT family
of signaling proteins, plays a pivotal role in the progression of
many human cancers, including acute myeloid leukemia and prostate
cancer. Unlike STAT3, where significant medicinal effort has been
expended to identify potent direct inhibitors, Stat5 has been poorly
investigated as a molecular therapeutic target. Thus, in an effort
to identify direct inhibitors of STAT5 protein, we conducted an <i>in vitro</i> screen of a focused library of SH2 domain binding
salicylic acid-containing inhibitors (∼150) against STAT5,
as well as against STAT3 and STAT1 proteins for SH2 domain selectivity.
We herein report the identification of several potent (<i>K</i><sub>i</sub> < 5 μM) and STAT5 selective (>3-fold specificity
for STAT5 cf. STAT1 and STAT3) inhibitors, <b>BP-1-107</b>, <b>BP-1-108</b>, <b>SF-1-087</b>, and <b>SF-1-088</b>. Lead agents, evaluated in K562 and MV-4-11 human leukemia cells,
showed potent induction of apoptosis (IC<sub>50</sub>’s ∼
20 μM) which correlated with potent and selective suppression
of STAT5 phosphorylation, as well as inhibition of STAT5 target genes <i>cyclin D1</i>, <i>cyclin D2</i>, <i>C-MYC</i>, and <i>MCL-1</i>. Moreover, lead agent <b>BP-1-108</b> showed negligible cytotoxic effects in normal bone marrow cells
not expressing activated STAT5 protein. Inhibitors identified in this
study represent some of the most potent direct small molecule, nonphosphorylated
inhibitors of STAT5 to date