Potent reversible inhibitors of the protein tyrosine phosphatase CD45

The cytosolic portion of CD45, a major transmembrane glycoprotein found on nucleated hematopoietic cells, contains protein tyrosine phosphatase activi ty and is critical for T-cell receptor-mediated T-cell activation. CD45 inh ibitors could have utility in the treatment of autoimmune disorders and org an graft rejection. A number of 9, l0-phenanthrenediones were identified th at reversibly inhibited CD45-mediated p-nitrophenyl phosphate (pNPP) hydrol ysis. Chemistry efforts around the 9,10-phenanthrenedione core led to the m ost potent inhibitors known to date. In a functional assay, the compounds w ere 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 phenanthrene dione pharmacophore could affect selectivity for CD45 over PTP1B (protein t yrosine phosphatase 1B) or vice versa.