Other PTP Inhibitors

PTP1B was the founding member of the PTP family, and a large amount of structural and mechanistic information is

Figure 3 Structures of potent and selective bidentate PTP1B inhibitors.

available for PTP1B. Furthermore, biochemical and genetic data suggest that PTP1B is a negative regulator for both insulin and leptin signaling. Consequently, most of the PTP inhibitors that are reported in the literature are directed to PTP1B. However, other PTPs have also received considerable attention, notably CD45 and Cdc25. Most of the inhibitors described earlier for CD45 and Cdc25 display only modest potency (~ 10 |iM) with very limited selectivity [55-57]. Many of them were identified from natural product screens. In most cases, the manner in which these compounds interact with the target PTPs is unclear, rendering structure-based optimization of new analogs difficult. A recent high-throughput evaluation of 10,070 compounds in a publicly available chemical repository of the National Cancer Institute led to the discovery of NSC 95397 (2,3-to-[2-hydroxyethylsulfanyl]-[1,4]naphthoquinone) (Fig. 4, compound 25), which displayed mixed inhibition kinetics, with in vitro Ki values for Cdc25A, -B, and -C of 32, 96, and 40 nM, respectively [58]. Compound 25 showed significant growth inhibition against human and murine carcinoma cells and blocked G2/M phase transition. Medicinal chemistry efforts around the 9,10-phenanthrenedione core resulted in potent CD45 inhibitors (Fig. 4, compound 26), some of which inhibit T-cell-receptor-mediated proliferation with activities in the low micromolar range [59]. Interestingly, suramin (Fig. 4, compound 27), one of the oldest synthetic therapeutics, which has long been used for the treatment of sleeping sickness and onchocerciasis, has been shown to be a potent reversible and competitive inhibitor of PTPs [60]. This is consistent with the observation that suramin leads to enhanced levels of tyrosine phosphory-lation in several cell lines. More recently, sodium stibogluconate (Fig. 4, compound 28), a pentavalent antimonial used for the treatment of leishmaniasis, has been suggested as a potent inhibitor of PTPs [61]. Although sodium stiboglu-conate augments cytokine responses in hemopoietic cell lines, its exact mode of action against PTPs is not clear and requires further investigation.

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