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Selective Protein Tyrosine Phosphatase 1B Inhibitors: Targeting the Second Phosphotyrosine Binding Site with Non-Carboxylic Acid-Containing Ligands

2003; American Chemical Society; Volume: 46; Issue: 16 Linguagem: Inglês

10.1021/jm034088d

1520-4804

Gang Liu, Zhili Xin, Heng Liang, Cele Abad‐Zapatero, Philip J. Hajduk, David A. Janowick, Bruce G. Szczepankiewicz, Zhonghua Pei, Charles W. Hutchins, Stephen J. Ballaron, Michael A. Stashko, Thomas Lübben, Cathy Berg, Cristina M. Rondinone, James M. Trevillyan, Michael R. Jirousek,

Bioactive Compounds and Antitumor Agents

Protein tyrosine phosphatase (PTPase) 1B (PTP1B) has been implicated as a key negative regulator of both insulin and leptin signaling cascades. We identified several salicylic acid-based ligands for the second phosphotyrosine binding site of PTP1B using a NMR-based screening. Structure-based linking with a catalytic site-directed oxalylarylaminobenzoic acid-based pharmacophore led to the identification of a novel series of potent PTP1B inhibitors exhibiting 6-fold selectivity over the highly homologous T-cell PTPase (TCPTP) and high selectivity over other phosphatases.