ArticleACS chemical biology2012
Inhibition of hematopoietic protein tyrosine phosphatase augments and prolongs ERK1/2 and p38 activation.
Article in ACS chemical biology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 34 citations in OpenAlex.
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- Investigating Mammalian Formins with SMIFH2 Fifteen Years in: Novel Targets and Unexpected Biology.International journal of molecular sciences · 2023Review
- A New Paradigm for KIM-PTP Drug Discovery: Identification of Allosteric Sites with Potential for Selective Inhibition Using Virtual Screening and LEI Analysis.International journal of molecular sciences · 2021Article
- Role of ETS1 in the Transcriptional Network of Diffuse Large B Cell Lymphoma of the Activated B Cell-Like Type.Cancers · 2020Article
- A cellular target engagement assay for the characterization of SHP2 (PTPN11) phosphatase inhibitors.The Journal of biological chemistry · 2020Article
- Physiologically relevant orthogonal assays for the discovery of small-molecule modulators of WIP1 phosphatase in high-throughput screens.The Journal of biological chemistry · 2019Article
- A high-throughput screen to identify novel small molecule inhibitors of the Werner Syndrome Helicase-Nuclease (WRN).PloS one · 2019Article
- Bidirectional Role of β2-Adrenergic Receptor in Autoimmune Diseases.Frontiers in pharmacology · 2018Review
- The KIM-family protein-tyrosine phosphatases use distinct reversible oxidation intermediates: Intramolecular or intermolecular disulfide bond formation.The Journal of biological chemistry · 2017Article
- Article
- Inhibitor of the tyrosine phosphatase STEP reverses cognitive deficits in a mouse model of Alzheimer's disease.PLoS biology · 2014Article
- High-throughput screening for protein tyrosine phosphatase activity modulators.Methods in molecular biology (Clifton, N.J.) · 2013Article
- Small molecule tools for functional interrogation of protein tyrosine phosphatases.The FEBS journal · 2013Review
- Protein tyrosine phosphatases: structure, function, and implication in human disease.Methods in molecular biology (Clifton, N.J.) · 2013Review
- Evaluating effects of tyrosine phosphatase inhibitors on T cell receptor signaling.Methods in molecular biology (Clifton, N.J.) · 2013Article
- Protein phosphatases and Alzheimer's disease.Progress in molecular biology and translational science · 2012Review
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Authors and funding
21 authors at 1 institution in 1 country.
Funding
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.
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