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CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Structurally Unique Inhibitors of Human Mitogen-Activated Protein Kinase Phosphatase-1 Identified in a Pyrrole Carboxamide Library

The Pittsburgh Molecular Libraries Screening Center (J.S.L., J.J.S., I.B., K.M.B.), University of Pittsburgh Drug Discovery Institute (J.S.L., J.J.S., F.K., A.Y.-D.), I.B., K.M.B.), Departments of Pharmacology (J.S.L., J.J.S., F.K., A.Y.-D.), Chemistry (S.W., B.M., K.M.B.), and Computational Biology (A.B., I.B.), and Center for Chemical Methodologies and Library Development (S.W., K.M.B.), University of Pittsburgh, Pittsburgh, Pennsylvania

Mitogen-activated protein kinase phosphatase 1 (MKP-1) is a tyrosine phosphatase superfamily member that dephosphorylates and inactivates cardinal mitogen-activated protein kinase (MAPK) substrates, such as p38, c-Jun NH₂-terminal kinase, and extracellular signal-regulated kinase. Although these MAPK substrates regulate many essential cellular processes associated with human diseases, few pharmacological inhibitors have been described. The lack of readily available selective MKP-1 inhibitors has severely limited interrogation of its biological role and was one rationale for using a recently described tricyclic pyrrole-2-carboxamide library in our screening efforts. In this report we demonstrate the pharmacological richness of the pyrrole carboxamide library by the finding that 10 of 172 members inhibited human MKP-1. Two of the pyrrole carboxamides, PSI2106 and MDF2085, were especially notable in vitro inhibitors of recombinant human MKP-1 enzyme activity with IC₅₀ values of 8.0 ± 0.9 and 8.3 ± 0.8 µM, respectively. Both showed some selectivity for MKP-1 over the closely related phosphatases MKP-3, Cdc25B, VHR, and PTP1B. Computational examination of the surface properties near the catalytic site revealed that the phosphatases studied differ significantly in their electrostatic potential at the substrate binding site. The compounds inhibited MKP-1 reversibly but displayed mixed kinetics. Phosphatase inhibition was retained in the presence of physiologically relevant concentrations of glutathione. Molecular docking studies suggested that PSI2106 may interact with His²²⁹ and Phe²⁹⁹ on MKP-1. These results reveal the power of using a small focused library for identifying pharmacological probes.

Address correspondence to: Dr. John S. Lazo, Pittsburgh Molecular Libraries Screening Center, Department of Pharmacology, University of Pittsburgh Drug Discovery Institute, Biomedical Science Tower-3, Suite 10040, 3401 Fifth Ave., University of Pittsburgh, Pittsburgh, PA 15260. E-mail: lazo{at}pitt.edu

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