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

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

doi:10.1016/j.bmc.2018.09.022

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. Epub 2018 Sep 19.

Authors

Bonsu Ku¹, Hye-Yeoung Yun¹, Kyung Won Lee², Ho-Chul Shin³, Sang-Rae Lee⁴, Chang Hyen Kim⁵, Hwangseo Park⁶, Kyu Yang Yi⁷, Chang Hoon Lee⁸, Seung Jun Kim⁹

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetamides / chemistry
Acetamides / pharmacology*
Cell Differentiation / drug effects
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Molecular Structure
Monocytes / drug effects
Osteoclasts / drug effects*
Osteoclasts / metabolism
Receptor-Like Protein Tyrosine Phosphatases, Class 4 / antagonists & inhibitors*
Receptor-Like Protein Tyrosine Phosphatases, Class 4 / metabolism
Structure-Activity Relationship
Thiadiazoles / chemistry
Thiadiazoles / pharmacology*

Substances

Acetamides
Enzyme Inhibitors
Thiadiazoles
1,3,4-thiadiazole
acetamide
PTPRE protein, human
Receptor-Like Protein Tyrosine Phosphatases, Class 4