Concluding Remarks

The importance of PTPs in the regulation of cellular signaling is well established. In spite of the large number of PTPs identified to date and the emerging roles played by PTPs in human diseases, a detailed understanding of the role played by PTPs in normal physiology and in pathogenic conditions has been hampered by the absence of PTP-specific agents. Such PTP-specific inhibitors could potentially serve as useful tools in determining the physiological significance of protein tyrosine phosphorylation in complex cellular signal transduction pathways and may constitute valuable therapeutics in the treatment of several human diseases. Despite the difficulties in obtaining such compounds, there are now several relatively specific inhibitors for PTP1B. It appears that significant differences exist within the active site and the immediate surroundings of various PTPs such that selective, tight-binding PTP inhibitors can be developed. In principle, an identical approach (i.e., to create bidentate inhibitors that could span both the active site and a unique adjacent peripheral site) used for PTP1B could also be employed to produce specific small-molecule inhibitors for all members of the PTP family that would enable the pharmacological modulation of selected signaling pathways for treatment of various diseases. Combinatorial solid-phase library synthesis is





ipH20H (j:H20H

Hpo COO'

Figure 4 Other PTP inhibitors.

finding wide applicability throughout the pharmaceutical industry, and, not surprisingly, this technique has begun to yield fruitful results in the area of PTP inhibitors.


Work in the author's laboratory was supported by Grants CA69202 and AI48506 from the National Institutes of Health, and by the G. Harold and Leila Y. Mathers Charitable Foundation.


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