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The Use of Chemical Inhibitors

Until now much of the published data on CD45 PTPase inhibitors has been reported as an adjunct to results presented on the inhibition of other PTPases (Lee and Burke 2003). The non-availability of CD45 crystal structures illustrating PTPase active site interactions with inhibitors has also hindered rational drug design. Nevertheless, certain classes of compounds have been shown to be potent inhibitors of CD45, and their actions in cell-based systems, at least in the T lineage, are consistent with the dominantly positive role of CD45 in regulating receptor signalling.

A variety of reagents, which may be divided into metal-containing or non-metal-containing, exert inhibitory effects on a broad range of PTPases, including CD45, but their lack of specificity render them of less interest in the therapeutic context (Lee and Burke 2003). For example, suramin is a potent inhibitor of CD45, with complete inhibition within 10 min at low micromolar concentrations, but it also inhibits a wide range of other PTPases (Ghosh and Miller 1993). Small molecules such as peroxynitrite (Takakura et al. 1999) and sulphotyrosyl peptides (Desmarais et al. 1998) are also nonspecific CD45 inhibitors

Various classes of phosphorus-containing analogues have been shown to be effective CD45 inhibitors, such as the phosphonate-containing class of small molecule inhibitors. These include nitroarylhydroxymethylphosphonic acid derivatives which demonstrate low micromolar affinity (IC50 values ranging from 2 to 12 ^M) against CD45 together with some selectivity for CD45 when compared to PTP1B (Beers et al. 1997). The arylmethylphospho-nic moieties in such compounds act as surrogates of phenylphosphate functionality. In contrast, a variety of compounds have been identified through natural product screens that do not contain phosphorus. For example, the aporphine alkaloid nornuciferine from Rollinia ulei extracts shows an IC50 of 5.3 ^M towards CD45 (Miski et al. 1995). Screening of Streptomyces extracts led to the discovery of the hydroquinone dephostatin that inhibits CD45 with an IC50 of 7.7 ^M (Imoto et al. 1993; Watanabe et al. 1995). An unsaturated lactam called pulchellalactam was isolated from the marine fungus Corollospora pulchella and displayed selectivity in inhibiting CD45 as compared to PTP1B (Alvi et al. 1998).

Small molecule screens have generated some non-phosphorus-containing compounds that show some promise as selective CD45 inhibitors. The benzimidazole derivative TU-572 inhibits CD45 with an IC50 of 0.28 ^M (Hamaguchi et al. 2000) and shows considerable specificity in comparison with a range of other phosphatases. The compound was also shown to suppress IgE-mediated anaphylaxis and murine contact hypersensitivity reactions (Hamaguchi et al. 2001). Derivatives of phenanthrenediones have also been found to be potent and reversible CD45 inhibitors at low micromolar concentrations, inhibiting T cell proliferation in biological assays (Urbanek et al. 2001).

Although the achievements in the field of CD45 inhibition have been somewhat modest relative to other PTPases, it is expected that the availability of crystal structures will accelerate the search for biologically relevant and selective inhibitors. A focused effort in this direction may well prove rewarding.

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