Discovery Of Small Molecular Inhibitors Of Protein Tyrosine Phosophatase 1B (PTP1B) From Traditional Chinese Medicinal Herbs

Protein tyrosine phosphatase 1B (PTP1B), as a typical non-receptor type member ofthe family of PTPs (protein tyrosine phosphatases, PTP), is a key element in thenegative regulation of insulin signaling pathway, and also has been a novel drugtarget for diabetes and obesity. Discovery for highly effective inhibitors of PTP1B hasa promising application in diabetes and obesity therapy.We developed a high-throughput screening assay of PTP1B. After screening thenational chemical library, we got 19 positive compounds of PTP1B. Ursolic acid, asone of the hits, is natural product extracted from the fruit of Cornus officinalis, whichis often used in traditional Chinese medicinal herbs. By structural optimization, weisolated a novel derivative, UA0713, almost 10-fold more potent than that of ursolicacid. We further determined inhibitor modality of UA0713 for PTP1B. UA0713inhibited PTP1B with typical characteristics of a competitive inhibitor, with a Ki of283 nM. The selectivity of the two compounds on other PTPs was also tested. Ursolicacid and UA0713 showed selective inhibition on PTP1B, TCPTP (T-cell proteintyrosine phosphatase) and SHP2 (SH-2 domain containing tyrosine phosphase), butno apparent inhibitory activity towards receptor-like transmembrane phosphatasessuch as LAR (leukocyte antigen related tyrosine phosphatase), PTPα (protein tyrosinephasphatase α) and PTPε (protein tyrosine phasphatase ε).We also evaluated the biological activity on the cellular level includingCHO/hIR cells (Chinese hamster ovary cell line transfected with an expressionplasmid encoding human IR) and rat L6 myotubes. UA0713 enhanced insulinreceptor phosphorylation in CHO/hIR cells and stimulated glucose uptake in L6myotubes. UA0713 showed no cytotoxicity by MTT method.We hope to optimize their structures further with the aim of increasing theirpotency and selectivity, as well as their efficiency in vivo. It has a promisingapplication to discovery novel lead compounds for diabetes and obesity therapy.