Identification of N-(5-(phenoxymethyl)-1,3,4-thiadiazol-2-yl)acetamide derivatives as novel protein tyrosine phosphatase epsilon inhibitors exhibiting anti-osteoclastic activity |
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| Authors: | Bonsu Ku Hye-Yeoung Yun Kyung Won Lee Ho-Chul Shin Sang-Rae Lee Chang Hyen Kim Hwangseo Park Kyu Yang Yi Chang Hoon Lee Seung Jun Kim |
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| Affiliation: | 1. Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea;2. Department of Bioscience, University of Science and Technology KRIBB School, Daejeon 34113, Republic of Korea;3. Center for Information-Based Drug Research, Bio and Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea;4. Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea;5. National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Republic of Korea;6. Department of Oral and Maxillofacial Surgery, Seoul St Mary’s Hospital, The Catholic University of Korea, Seoul 06591, Republic of Korea;7. Department of Bioscience and Biotechnology, Sejong University, Seoul 05006, Republic of Korea |
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| 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. |
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| Keywords: | 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 |
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