Discovery of novel arylpyridine derivatives for motile ciliogenesis.

Autor: Lee GB; Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea., Chandrasekaran G; Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea., Kim HJ; Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea; Department of Microbiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea., Kim P; Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea., Yoon J; Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea., Choi BW; Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea., Lee SH; Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea., Lee SY; Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea; Department of Microbiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea., Shin DS; Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, Korea, Republic of Korea., Lee BH; Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, Korea, Republic of Korea., Bae MA; Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, Korea, Republic of Korea., Goughnour P; JD Bioscience, 208 Cheomdan-dwagiro, Buk-gu, Gwangju, 61005, Republic of Korea., Choi EY; Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea; Department of Microbiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea. Electronic address: choieun@amc.seoul.kr., Choi SY; Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea. Electronic address: zebrafish@chonnam.ac.kr., Ahn JH; Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea; JD Bioscience, 208 Cheomdan-dwagiro, Buk-gu, Gwangju, 61005, Republic of Korea. Electronic address: jhahn@gist.ac.kr.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2024 Nov 05; Vol. 277, pp. 116764. Date of Electronic Publication: 2024 Aug 13.
DOI: 10.1016/j.ejmech.2024.116764
Abstrakt: Motile cilia are crucial for maintaining healthy bodily functions by facilitating fluid transport and removing foreign substances or debris from the body. The dysfunction of motile cilia leads to ciliopathy. In particular, damage to the motile cilia of the airways can cause or worsen respiratory disease, making it an attractive target for therapeutic interventions. However, there are no treatments to induce motile ciliogenesis. Forkhead box transcription factor J1 (FOXJ1), the master regulator, has been implicated in motile cilia formation. Mice lacking the Foxj1 gene show loss of axoneme, a key component of cilia, that further highlights the importance of FOXJ1 in motile cilia formation. This prompted us to identify new small molecules that could induce motile ciliogenesis. A phenotype-based high-throughput screening (HTS) in a Tg(foxj1a:eGFP) zebrafish model was performed and a novel hit compound was identified. Among the synthesized compounds, compound 16c effectively enhanced motile ciliogenesis in a transgenic zebrafish model. To further test the efficacy of compound 16c on a mammalian airway system consisting of multiciliated cells (MCCs), ex vivo mice tracheal epithelial cell culture was adopted under an air-liquid interface system (ALI). Compound 16c significantly increased the number of MCCs by enhancing motile ciliogenesis. In addition, compound 16c exhibited good liver microsomal stability, in vivo PK profiles with AUC, and oral bioavailability. There was no significant inhibition of CYP and hERG, and no cell cytotoxicity was shown. In an elastase-induced COPD (chronic obstructive pulmonary disease) mouse model, compound 16c effectively prevented the development and onset of COPD. Taken together, compound 16c has great promise as a therapeutic agent for treating and alleviating motile ciliopathies.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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