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Urbanek, Rebecca A; Suchard, Suzanne J; Steelman, Gary B; Knappenberger, Katharine S; Sygowski, Linda A; Veale, Chris A; Chapdelaine, Marc J
Journal of medicinal chemistry, 05/2001, Letnik: 44, Številka: 11Journal Article
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.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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