- Potent reversible inhibitors of the protein tyrosine phosphatase CD45
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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-ediated 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.
- Urbanek,Suchard,Steelman,Knappenberger,Sygowski,Veale,Chapdelaine
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- COMPOSITIONS AND METHODS OF MAKING EXPANDED HEMATOPOIETIC STEM CELLS USING PTEN INHIBITORS
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This invention is directed to, inter alia, compounds, methods, systems, and compositions for the maintenance, enhancement, and expansion of hematopoietic stem cells derived from sources of non-mobilized peripheral blood. Also provided herein are compounds of Formula I which are useful in maintaining, enhancing, and expanding of hematopoietic stem cells.
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Paragraph 0314
(2018/12/13)
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- PTEN INHIBITORS
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The therapeutic use of inhibitors of PTEN activity in the treatment of PTEN-mediated diseases, conditions, and injuries is disclosed.
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Page/Page column 76
(2008/06/13)
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- Cd45 inhibitors
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Substituted phenanthrene-9,10-diones in accord with structural diagram I, 1compositions thereof and methods for the use thereof, for the treatment of T cell mediated conditions such as autoimmune diseases and organ graft rejection. In compounds of the invention, R1 at each occurrence is independently selected from hydrogen, halogen, NH-tosyl, N-di-tosyl, NH2, NO2, NH—CO—R2, CO—NH—R2, Ar, (CH2)nCH(COOH)R3 COR3 and NHCOCH2CH(COOH)NHR4, where R2, R3 and R4 are a selected from a variety of substituted or unsubstituted alkyl and aryl groupstand oligopeptides.
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