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Title 

Identification of N-(5-(phenoxymethyl)-1,3,4-thiadiazol-2-yl)acetamide derivatives as novel protein tyrosine phosphatase epsilon inhibitors exhibiting anti-osteoclastic activity

Authors 

Bonsu KuHye-Yeoung YoonKyuong Won LeeHo Chul ShinSang-Rae LeeC H KimH ParkK Y LeeChang Hoon LeeSeung Jun Kim

Publisher 

Elsevier

Issue Date 

2018

Citation 

Bioorganic & Medicinal Chemistry

Keywords 

InhibitorOsteoclastPTPεPodosomeProtein tyrosine phosphatase

Abstract 

Cytosolic protein tyrosine phosphatase epsilon (cyt-PTPε) plays a central role in controlling differentiation and function of osteoclasts, whose overactivation causes osteoporosis. Based on our previous study reporting a number of cyt-PTPε inhibitory chemical compounds, we carried out a further and extended analysis of our compounds to examine their effects on cyt-PTPε-mediated dephosphorylation and on osteoclast organization and differentiation. Among five compounds showing target selectivity to cyt-PTPε over three other phosphatases in vitro, two compounds exhibited an inhibitory effect against the dephosphorylation of cellular Src protein, the cyt-PTPε substrate. Moreover, these two compounds caused destabilization of the podosome structure that is necessary for the bone-resorbing activity of osteoclasts, and also attenuated cellular differentiation of monocytes into osteoclasts, without affecting cell viability. Therefore, these findings not only verified anti-osteoclastic effects of our cyt-PTPε inhibitory compounds, but also showed that cyt-PTPε expressed in osteoclasts could be a putative therapeutic target worth considering.

ISSN 

0968-0896

Link 

http://dx.doi.org/10.1016/j.bmc.2018.09.022

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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