5 research outputs found
Inhibition of Hematopoietic Protein Tyrosine Phosphatase Augments and Prolongs ERK1/2 and p38 Activation
The hematopoietic protein tyrosine phosphatase (HePTP)
is implicated
in the development of blood cancers through its ability to negatively
regulate the mitogen-activated protein kinases (MAPKs) ERK1/2 and
p38. Small-molecule modulators of HePTP activity may become valuable
in treating hematopoietic malignancies such as T cell acute lymphoblastic
leukemia (T-ALL) and acute myelogenous leukemia (AML). Moreover, such
compounds will further elucidate the regulation of MAPKs in hematopoietic
cells. Although transient activation of MAPKs is crucial for growth
and proliferation, prolonged activation of these important signaling
molecules induces differentiation, cell cycle arrest, cell senescence,
and apoptosis. Specific HePTP inhibitors may promote the latter and
thereby may halt the growth of cancer cells. Here, we report the development
of a small molecule that augments ERK1/2 and p38 activation in human
T cells, specifically by inhibiting HePTP. Structure–activity
relationship analysis, <i>in silico</i> docking studies,
and mutagenesis experiments reveal how the inhibitor achieves selectivity
for HePTP over related phosphatases by interacting with unique amino
acid residues in the periphery of the highly conserved catalytic pocket.
Importantly, we utilize this compound to show that pharmacological
inhibition of HePTP not only augments but also prolongs activation
of ERK1/2 and, especially, p38. Moreover, we present similar effects
in leukocytes from mice intraperitoneally injected with the inhibitor
at doses as low as 3 mg/kg. Our results warrant future studies with
this probe compound that may establish HePTP as a new drug target
for acute leukemic conditions