title: Potent reversible inhibitors of the protein tyrosine phosphatase CD45.
abstract: The cytosolic portion of CD45, a major transmembrane glycoprotein found on nucleated hematopoietic cells, contains protein tyrosine phosphatase activity and is critical for T-cell receptor-mediated T-cell activation. CD45 inhibitors could have utility in the treatment of autoimmune disorders and organ graft rejection. A number of 9,10-phenanthrenediones were identified that reversibly inhibited CD45-mediated p-nitrophenyl phosphate (pNPP) hydrolysis. Chemistry efforts around the 9,10-phenanthrenedione core led to the most potent inhibitors known to date. In a functional assay, the compounds were also potent inhibitors of T-cell receptor-mediated proliferation, with activities in the low micromolar range paralleling their enzyme inhibition. It was also discovered that the nature of modification to the phenanthrenedione pharmacophore could affect selectivity for CD45 over PTP1B (protein tyrosine phosphatase 1B) or vice versa.
authors.affiliation: AstraZeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, Delaware 19850, USA. rebecca.urbanek@astrazeneca.com
authors.forename: R A
authors.initials: RA
authors.lastname: Urbanek
authors.forename: S J
authors.initials: SJ
authors.lastname: Suchard
authors.forename: G B
authors.initials: GB
authors.lastname: Steelman
authors.forename: K S
authors.initials: KS
authors.lastname: Knappenberger
authors.forename: L A
authors.initials: LA
authors.lastname: Sygowski
authors.forename: C A
authors.initials: CA
authors.lastname: Veale
authors.forename: M J
authors.initials: MJ
authors.lastname: Chapdelaine
mesh_terms: D002455:Cell Division; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D017493:Leukocyte Common Antigens / Q000737:chemistry / Q000378:metabolism*; D009285:Naphthoquinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009596:Nitrophenols / Q000737:chemistry; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000737:chemistry; D010616:Phenanthrenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D009285:Naphthoquinones; D009596:Nitrophenols; D009842:Oligopeptides; D009943:Organophosphorus Compounds; D010616:Phenanthrenes; C008644:nitrophenylphosphate; D017493:Leukocyte Common Antigens; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases