Identification of N-(5-(phenoxymethyl)-1, 3, 4-thiadiazol-2-yl)acetamide derivatives as novel protein tyrosine phosphatase epsilon inhibitors exhibiting anti-osteoclastic activity. Issue 18 (1st October 2018)

• Record Type: Journal Article
• Authors: Ku, Bonsu; Yun, Hye-Yeoung; Lee, Kyung Won; Shin, Ho-Chul; Lee, Sang-Rae; Kim, Chang Hyen; Park, Hwangseo; Yi, Kyu Yang; Lee, Chang Hoon; Kim, Seung Jun
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 18(2018)
• Page Start: 5204
• Page End: 5211
• Publication Date: 2018-10-01
• Subjects: PTP protein tyrosine phosphatase -- c-Src cellular proto-oncogene tyrosine kinase Src -- RANKL receptor activator of nuclear factor kappa-β ligand -- cyt-PTPε cytosolic PTP epsilon -- TRAP tartrate-resistant acid phosphatase -- M-CSF monocyte colony-stimulating factor -- α-MEM minimum essential medium alpha -- FBS fetal bovine serum -- BSA bovine serum albumin -- TBST Tris-buffered saline with Tween-20 -- PBS phosphate-buffered saline; PTPε -- Protein tyrosine phosphatase -- Inhibitor -- Osteoclast -- Podosome; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.09.022
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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.