Inhibition of Hematopoietic Protein Tyrosine Phosphatase Augments and Prolongs ERK1/2 and p38 Activation

Abstract

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, in silico 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.

Small molecule tools for functional interrogation of protein tyrosine phosphatases

“…Compound 20 contains a 2H‐thiazolo[3,2‐α]pyrimidin‐3(5H)‐one core structure with a phenoxyacetic acid headgroup, and exhibits an IC 50 of 1.0 μ m for HePTP, showing 19.5‐ and 42‐fold selectivity over VHR and MKP‐3, respectively. To find additional HePTP inhibitors, HePTP was screened within the Molecular Library Probe Production Center Network, which led to the identification of compound 21 [79]. Compound 21 (Fig.…”

Protein Phosphatases and Alzheimer's Disease

“…In studies with the closely related phosphatase HePTP, a selective small-molecule inhibitor was found to interact specifically with the corresponding histidine residue in HePTP. 246 Several pharmaceutical companies have begun drug discovery programs to identify STEP inhibitors that will hopefully be available for preclinical studies in the near future.…”

Medicinal Chemistry in the Context of the Human Genome

“…The phosphatases share a high homology at the catalytic center and therefore structural information is crucial for the design of selective ligands. Recently, more selective inhibitors have been identified for PTP1B, hematopoietic protein tyrosine phosphatase (HePTP), lymphoid PTP (LYP), and Src homology 2 domain-containing PTP (SHP2), all of which are bidentate and target the active center with a carboxylic acid moiety and an adjacent binding pocket with a lipophilic (aromatic) moiety [55][56][57][58][59]. Structures of the catalytic domains from all of the PTP subfamilies have been published by the SGC [60].…”