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

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

  • Bioorg Med Chem. 2018 Oct 1;26(18):5204-5211. doi: 10.1016/j.bmc.2018.09.022.
Bonsu Ku 1,  Hye-Yeoung Yun 1,  Kyung Won Lee 2,  Ho-Chul Shin 3,  Sang-Rae Lee 4,  Chang Hyen Kim 5,  Hwangseo Park 6,  Kyu Yang Yi 7,  Chang Hoon Lee 8,  Seung Jun Kim 9
Affiliations

Affiliations

  • 1 Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea; Department of Bioscience, University of Science and Technology KRIBB School, Daejeon 34113, Republic of Korea.
  • 2 Center for Information-Based Drug Research, Bio and Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea; Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea.
  • 3 Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea.
  • 4 National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Republic of Korea.
  • 5 Department of Oral and Maxillofacial Surgery, Seoul St Mary's Hospital, The Catholic University of Korea, Seoul 06591, Republic of Korea.
  • 6 Department of Bioscience and Biotechnology, Sejong University, Seoul 05006, Republic of Korea.
  • 7 Center for Information-Based Drug Research, Bio and Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
  • 8 Center for Information-Based Drug Research, Bio and Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea; Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea. Electronic address: lee2014@krict.re.kr.
  • 9 Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea; Department of Bioscience, University of Science and Technology KRIBB School, Daejeon 34113, Republic of Korea. Electronic address: ksj@kribb.re.kr.
PMID: 30249496 DOI: 10.1016/j.bmc.2018.09.022
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.

Keywords

Inhibitor; Osteoclast; PTPε; Podosome; Protein tyrosine phosphatase.

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