Small molecule tools for functional interrogation of protein tyrosine phosphatases

Abstract

The importance of protein tyrosine phosphatases (PTPs) in the regulation of cellular signaling is well established. Malfunction of PTP activity is also known to be associated with cancer, metabolic syndromes, autoimmune disorders, neurodegenerative and infectious diseases. However, a detailed understanding of the roles played by the PTPs in normal physiology and in pathogenic conditions has been hampered by the absence of PTP-specific small molecule agents. In addition, the therapeutic benefits of modulating this target class are underexplored due to lack of suitable chemical probes. Potent and specific PTP inhibitors could significantly facilitate functional analysis of the PTPs in complex cellular signal transduction pathways and may constitute valuable therapeutics in the treatment of several human diseases. We will highlight the current challenges and opportunities in developing PTP-specific small molecule agents. We will also review available selective small molecule inhibitors developed for a number of PTPs, including PTP1B, TC-PTP, SHP2, Lyp, HePTP, CD45, PTPβ, PTPγ, PTPRO, VHR, MKP-1, MKP-3, Cdc25, YopH, mPTPA, and mPTPB.

Protein Tyrosine Phosphatases in Hypothalamic Insulin and Leptin Signaling

“…These pTyr mimetics interact in the desired inhibitory fashion with the PTP active site and the molecular scaffolds attached to them render the inhibitors PTP isozyme-selective. Recent studies using fragment-based and structureguided approaches to target both the PTP active site and adjacent less conserved pockets demonstrate that it is feasible to obtain PTP inhibitors with high affinity, selectivity, and excellent in vivo efficacy in animal models of oncology, diabetes/obesity, autoimmunity, and tuberculosis [98]. In addition to the active site-directed approach, another promising method that has been gaining significant traction in PTP drug discovery is targeting allosteric sites in PTPs that are less conserved, which has been demonstrated to be a good strategy for the development of inhibitors with high specificity and cell permeability [92].…”

“PEST control”: regulation of molecular barcodes by tyrosine phosphatases

“…While this concept is not new, and has led to the successful design of bi-dentate and multi-dentate tyrosine phosphatase inhibitors with enhanced enzyme selectivity features [7], it is the first time that it is extended to selective targeting of phosphorylation sites within the same molecule. The Wang et al approach to phosphatase selectivity through structural biology paves the way to the rational design of compounds for selective inhibition of single site dephosphorylation, which would be desirable for biology studies and signaling therapies [8].…”

1H-2,3-Dihydroperimidine Derivatives: A New Class of Potent Protein Tyrosine Phosphatase 1B Inhibitors

“…Therefore, PTP1B seems to be a potential target for the treatment of type 2 diabetes mellitus, obesity, and cancer. A variety of PTP1B inhibitors have been disclosed among academic and industrial laboratories [15][16][17]. Two compounds, ertiprotafib and trodusquemine, have progressed to clinical trials [18,19].…”