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Title 

Identification of a novel SHP-2 protein tyrosine phosphatase inhibitor

Authors 

A JuH SeoH KimByoung Chul ParkSung Goo ParkJeong Hoon KimH K ChoiK H MinS Cho

Publisher 

Chemical Society of Japan

Issue Date 

2014

Citation 

Bulletin of the Chemical Society of Japan, vol. 87, no. 3, pp. 420-424

Abstract 

The Src homology 2 (SH2) domain-containing phosphatase 2 (SHP-2) is a nonreceptor protein tyrosine phosphatase (PTP) involved in extracellular- regulated kinase (ERK) activation. Recent studies have shown that gain-of-function mutations in SHP-2 are associated with several diseases, including LEOPARD syndrome, Noonan syndrome, and juvenile myelomonocytic leukemia. In this study, we identified the novel SHP-2 inhibitor 3-(1-benzimidazolylmethyl)-6-p-tolyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (MLS-001). SHP-2 activity was inhibited by MLS-001, whereas other types of PTPs, namely ACP1, CDC25A, DUSP3, DUSP14, DUSP18, DUSP22, DUSP23, DUSP26, and SSH3, were not. Furthermore, TCPTP and SHP-1 that are closely related to SHP-2 were not inhibited by the inhibitor. Kinetic studies with MLS-001 and SHP-2 revealed a competitive inhibition. The SHP-2 expressing cells treated with MLS-001 demonstrated reduced SHP-2 phosphatase activity, thereby suggesting that MLS-001 effectively passes through cell membranes. In addition, MLS-001 reduced SHP-2-mediated phosphorylation in the activation loop of ERK in cells. Therefore, MLS-001 could be a lead compound for developing a potent SHP-2 inhibitor.

ISSN 

0009-2673

Link 

http://dx.doi.org/10.1246/bcsj.20130221

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2017-04-19


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