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Proper level of protein tyrosine phosphorylation,coordinated by the reversible and dynamic action of protein tyrosine ki-nases (PTKs) and protein tyrosine phosphatases (PTPs),is essential for cell growth and survival.Aberrant protein tyrosine phosphorylation,due to perturbed balance between the activities of PTKs and PTPs,is linked to the etiology of numerous human diseases including cancer,metabolic syndromes,autoimmune disorders,neurodegenerative and neurological dis-eases.Consequently,signaling events driven by protein tyrosine phosphorylation offer a rich source of molecular targets for therapeutic interventions.The ability to selectively modulate signaling pathways,through inhibition of PTPs,holds enormous therapeutic potential.However,despite the fact that PTPs have been garnering attention as attractive drug tar-gets,they remain largely an untapped resource.Among the contributing factors to the challenge of targeting PTPs for drug discovery is the lack of detailed understanding of how dysregulation of PTP activity cause human diseases.In addition,the PTPs are exceptionally difficult targets for drug discovery due to the highly conserved and positively charged active sites.To facilitate therapeutic targeting of the PTPs,we have established a unique academic chemical genomic program encom-passing high-throughput screening,structure-based design,and medicinal chemistry to develop small molecule PTP probes for functional interrogation,target identification/validation,and therapeutic development.To this end,we have pioneered a novel paradigm for the acquisition of potent and selective PTP inhibitors by targeting both the PTP active site and unique pockets in the vicinity of the active site.We have developed a number of nonhydrolyzable pTyr pharmacophores that are sufficiently polar to bind the PTP active site,yet remain capable of efficiently crossing cell membranes,offering PTP inhib-itors with both high potency and excellent in vivo efficacy.Potent and specific PTP inhibitors could significantly facilitate functional analysis of the PTPs in complex cellular signal transduction pathways and may constitute valuable therapeutics for many human diseases.