Discovery of Novel Inhibitors of Dual-Specificity Phosphatase Pyst2 with Structure-Based Virtual Screening

Protein tyrosine phosphatases (PTPs) are a family of the regulatory enzymes that are responsible for the dephosphor-ylation of phosphotyrosine residues in the protein substrates. A series of experimental evidence has been reported so far to support the correlation between malfunctions in PTP activity and various diseases including cancer, neurological disorders, and diabetes.1 This has made PTPs be a promising target for drug discovery. Of the various PTPs, Pyst2 (also known as MKP-X and DUSP7) is a member of the Pyst subfamily of dual-specificity phosphatases (DUSPs) and known to have substrate selectivity for the classical p42 (ERK2) isoform of the mitogen-activated protein kinase (MAPK).2,3 Pyst2 was known to be overexpressed in leukemia and other malignant cells,4,5 which indicates that Pyst2 can be a target for the development of cancer drugs.6 Despite such a pharmaceutical importance, no small-molecule Pyst2 inhibi-tors has been reported so far. In this study, we identify two novel inhibitors of Pyst2 based on the structure-based drug design protocol involving the virtual screening with docking simulations and in vitro enzyme assay. It will be shown that the docking simulation with the improved scoring function can be a useful for elucidating the activities of the identified inhibitors, as well as for enriching the chemical library with molecules that are likely to have inhibitory activities.7 The docking library for Pyst2 comprising about 85,000 compounds was constructed from the chemical database distributed by Interbioscree