Allosteric noncompetitive small molecule selective inhibitors of CD45 tyrosine phosphatase suppress T-cell receptor signals and inflammation in vivo

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DOIResolve DOI: http://doi.org/10.1124/mol.113.089847
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TypeArticle
Journal titleMolecular Pharmacology
ISSN0026-895X
Volume85
Issue4
Pages553563; # of pages: 11
SubjectCD45 antigen; compound 211; interleukin 2; mitogen activated protein kinase; protein kinase Lck; protein kinase ZAP 70; protein tyrosine phosphatase inhibitor; T lymphocyte receptor; unclassified drug; animal cell; animal experiment; animal model; article; assay; binding site; cell activity; computer model; controlled study; cytokine production; delayed hypersensitivity; drug dose escalation; drug potency; drug selectivity; female; IC 50; immunosuppressive treatment; in vivo study; inflammation; lymphocytic infiltration; molecular docking; mouse; neutropenia; nonhuman; priority journal; protein dephosphorylation; signal transduction; single drug dose; site directed mutagenesis; spleen cell; T lymphocyte; Allosteric Regulation; Allosteric Site; Animals; Antigens, CD45; Cells, Cultured; Enzyme Activation; Female; Hypersensitivity, Delayed; Immunologic Factors; Immunosuppressive Agents; Inflammation; Interleukin-2; Lymphocyte Specific Protein Tyrosine Kinase p56(lck); Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; Molecular Docking Simulation; Mutagenesis, Site-Directed; Naphthoquinones; Phosphorylation; Phosphotyrosine; Receptors, Antigen, T-Cell; Signal Transduction; Structure-Activity Relationship; ZAP-70 Protein-Tyrosine Kinase
AbstractCD45 is a receptor-like member of the protein tyrosine phosphatase (PTP) family. We screened in silico for small molecules binding at a predicted allosteric pocket unique to the CD45 intracellular domain, and validated inhibitors by in vitro phosphatase assays. Compound 211 exhibited a CD45 IC 50 value of 200 nM and had >.100-fold selectivity over six related PTPs. The relevance of the allosteric pocket was verified through site-directed mutagenesis. Compound 211 has a noncompetitive mechanism of action, and it is extremely effective at preventing dephosphorylation of substrate Lck phosphotyrosine (pY)-505 versus preventing dephosphorylation of Lck pY-393. In cultured primary T cells, compound 211 prevents T-cell receptor-mediated activation of Lck, Zap-70, and mitogen-activated protein kinase, and interleukin-2 production. In a delayed-type hypersensitivity reaction in vivo, compound 211 abolished inflammation. This work demonstrates a novel approach to develop effective allosteric inhibitors that can be expanded to target the corresponding allosteric domains of other receptor PTPs.
Publication date
LanguageEnglish
AffiliationNational Research Council Canada (NRC-CNRC); NRC Biotechnology Research Institute (BRI-IRB)
Peer reviewedYes
NPARC number21272140
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Record identifier2cd1e146-72dc-458b-ade6-562045109eda
Record created2014-07-23
Record modified2016-05-09
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