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Bringing It All Together: Future Challenges

During the last few years there has been significant progress in the development of PTP inhibitors. Using structure-based design approaches, several groups have shown that it is possible to synthesize highly potent and selective non-phosphorus, non-peptide inhibitors of PTP1B. However, at this point these achievements seem to have been reached at the expense of appropriate pharmacokinetic properties, including cellular uptake. Therefore, the next wave within the field of PTP inhibitors is likely to be focused on improvements in this respect.

Furthermore, although very significant progress has been achieved with respect to design of selective PTP1B inhibitors (see Sect. 9), it remains to be demonstrated that drug-like PTP1B inhibitors can be made that do not recognize TC-PTP. TC-PTP is the closest homolog to PTP1B, sharing about 74 percent identity at the amino acid level in the catalytic domains. TC-PTP exists both as a 48-kDa endoplasmic reticulum-targeted form (TC48) and a 45-kDa nuclear form (TC45). Since both PTP1B and TC48 are bound to the endoplasmic reticulum via their C-terminal extensions, it might be speculated that these two PTPs serve similar, perhaps even overlapping, functions. Indeed, in a recent publication it was suggested that TC-PTP is involved in the regulation of insulin signaling (Galic et al. 2003). However, it should be noted that TC-PTP knockout mice, in contrast to PTP1B knockout mice (Elchebly et al. 1999; Klaman et al. 2000), die a few weeks after birth, whereas heterozygous mice seem to have normal lifespan (Ibarra-Sanchez et al. 2000). At present, it is therefore unclear if PTP1B inhibitors that also recognize TC-PTP will be beneficial or harmful. To provide the structural framework for design of inhibitors that are selective for either PTP1B or TC-PTP, we have recently reported the X-ray structure of apo TC-PTP (Iversen et al. 2002). Of note, and as indicated above, two groups have provided structure-based evidence that inhibitors that are selective for PTP1B over TC-PTP are within reach (see Sect. 9.3).

Another challenge facing the PTP field is the fact that PTPs themselves seem to be regulated by covalent modifications, e.g., phosphorylation. In particular, modifications close to the active site may influence not only sub strate, but also inhibitor binding. As an example, recent studies indicate that the activity of PTP1B may be influenced by phosphorylation of Ser50 (Ravichandran et al. 2001), which is positioned close to the selectivity-determining region defined by residues 47-48 and 258-259. It is quite likely that the position of the side chains of these residues will be influenced by a bulky, charged phosphate group on Ser50. Since all structure-based design activities up to this point have been carried out with catalytic domains produced in E. coli, it is suggested that future design efforts include testing of lead compounds either in appropriately covalently modified recombinant enzymes or in a relevant cellular context. It should also be mentioned that the activity of PTPs may be greatly influenced by domains outside the catalytic domains, and again this has to be taken into account in future PTP inhibitor development programs.

As has become apparent, almost all activities so far have been directed towards development of selective PTP1B inhibitors. However, several other classical PTPs and dual-specificity PTPs may be important novel drug targets, indicating that the focus on general PTP inhibitors may be a powerful platform for the discovery of novel therapeutics. Consistent with this concept, we have been able to use the original scaffold, OBA, as a template for synthesis of highly potent inhibitors of PTPb with significant selectivity over PTP1B, and pharmacological characterization of such compounds may reveal new biological insights and potential clinical applications (Lund et al. 2004).

Finally, it should be, emphasized that the discovery of the transient formation of sulphenyl-amide as described in Sect. 6 may represent an exiting new avenue for structure-based design of PTP inhibitors. The significant conformational changes imposed by the sulphenyl-amide in the active site prevent binding of pTyr substrates and probably all currently known active site-dependent inhibitors. The formation of the sulphenyl-amide is reversible, and it is believed to occur in vivo after stimulation of receptor-tyrosine kinases, resulting in H2O2 formation. Therefore, compounds that bind to the sulphenyl-amide form of PTPs, and not to the wild-type enzymes, are expected to inhibit already-activated signaling pathways only, thereby possibly providing an additional level of specificity and limiting the risk of side effects.

Acknowledgements The authors thank (1) James G. McCormack, OSI Pharmaceuticals, Karin Bach M0ller, Novo Nordisk, and Jannik N. Andersen (J.N.A.), Cold Spring Harbor Laboratory, for helpful discussions and critical reading of the manuscript; (2) J.N.A. for graphical assistance, and (3) Michael Jirousek, Gang Liu, and Cele Abad-Zapatero for sharing the coordinates of 1Q1 M with us prior to PDB release.

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