A polo-like kinase inhibitor identified by computational repositioning attenuates pulmonary fibrosis

• Material Type: 博士論文
• Title: A polo-like kinase inhibitor identified by computational repositioning attenuates pulmonary fibrosis
• Author/Editor: Imakura, Takeshi; Sato, Seidai; Koyama, Kazuya; Ogawa, Hirohisa; Niimura, Takahiro; Murakami, Kojin; Yamashita, Yuya; Haji, Keiko; Naito, Nobuhito; Kagawa, Kozo; Kawano, Hiroshi; Zamami, Yoshito; Ishizawa, Keisuke; Nishioka, Yasuhiko
• Author Heading: Imakura, Takeshi; Sato, Seidai; Koyama, Kazuya; Ogawa, Hirohisa; Niimura, Takahiro; Murakami, Kojin; Yamashita, Yuya; Haji, Keiko; Naito, Nobuhito; Kagawa, Kozo; Kawano, Hiroshi; Zamami, Yoshito; Ishizawa, Keisuke; Nishioka, Yasuhiko
• Publication, Distribution, etc.: Springer Nature|BioMed Central
• Publication Date: 2023-06-02
• Publication Date (W3CDTF): 2023-06-02
• Alternative Title: コンピュータ上でのドラッグ・リポジショニングにより同定したPLK阻害薬は肺線維化を抑制する
• Periodical title: Respiratory Research
• No. or year of volume/issue: 24
• Volume: 24
• Pages: 148-
• ISSN (Periodical Title): ISSN : 1465-993X
• Degree grantor/type: 徳島大学
• Date Granted: 2024-01-25
• Dissertation Number: 甲第3769号
• Degree Type: 博士（医学）
• Text Language Code: eng
• Subject Heading: Polo-like kinase; Pulmonary fibrosis; In silico screening; Myofibroblast; Lung epithelial cell
• Target Audience: 一般
• Note (General): Background: Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease with few effective therapeutic options. Recently, drug repositioning, which involves identifying novel therapeutic potentials for existing drugs, has been popularized as a new approach for the development of novel therapeutic reagents. However, this approach has not yet been fully utilized in the field of pulmonary fibrosis. Methods: The present study identified novel therapeutic options for pulmonary fibrosis using a systematic computational approach for drug repositioning based on integration of public gene expression signatures of drug and diseases (in silico screening approach). Results: Among the top compounds predicted to be therapeutic for IPF by the in silico approach, we selected BI2536, a polo-like kinase (PLK) 1/2 inhibitor, as a candidate for treating pulmonary fibrosis using an in silico analysis. However, BI2536 accelerated mortality and weight loss rate in an experimental mouse model of pulmonary fibrosis. Because immunofluorescence staining revealed that PLK1 expression was dominant in myofibroblasts while PLK2 expression was dominant in lung epithelial cells, we next focused on the anti-fibrotic effect of the selective PLK1 inhibitor GSK461364. Consequently, GSK461364 attenuated pulmonary fibrosis with acceptable mortality and weight loss in mice. Conclusions: These findings suggest that targeting PLK1 may be a novel therapeutic approach for pulmonary fibrosis by inhibiting lung fibroblast proliferation without affecting lung epithelial cells. In addition, while in silico screening is useful, it is essential to fully determine the biological activities of candidates by wet-lab validation studies.
• Access Restrictions: インターネット公開
• Rights (production): This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
• Related Material (DOI): 10.1186/s12931-023-02446-x
• Data Provider (Database): 国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）; https://irdb.nii.ac.jp
• Original Data Provider (Database): 徳島大学 : 徳島大学機関リポジトリ

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http://repo.lib.tokushima-u.ac.jp/files/public/11/119057/20240301145251202531/k3769_abstract.pdf fulltext

http://repo.lib.tokushima-u.ac.jp/files/public/11/119057/20240301145251294676/k3769_review.pdf fulltext

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