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Identification of a selective inhibitor of human monocarboxylate transporter 4

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Title: Identification of a selective inhibitor of human monocarboxylate transporter 4
Authors: Futagi, Yuya Browse this author
Kobayashi, Masaki Browse this author →KAKEN DB
Narumi, Katsuya Browse this author
Furugen, Ayako Browse this author
Iseki, Ken Browse this author →KAKEN DB
Keywords: Monocarboxylate transporter
Lactic acid
Issue Date: 1-Jan-2018
Publisher: Elsevier
Journal Title: Biochemical and biophysical research communications
Volume: 495
Issue: 1
Start Page: 427
End Page: 432
Publisher DOI: 10.1016/j.bbrc.2017.10.025
PMID: 28993194
Abstract: The human monocarboxylate transporters (hMCTs/SLC16As) mediate the uptake of various mono-carboxylates. Several isoforms of hMCTs are expressed in cancerous tissue as well as in normal tissue. In cancerous tissue, hypoxia induces the expression of hMCT4, which transports the energetic metabolite lactate across the plasma membrane. Since hMCT4 is involved in pH regulation and the transport of lactate in cancer cells, an hMCT4 inhibitor could function as an anticancer agent. Although several non specific hMCT inhibitors have been developed, a selective hMCT4 inhibitor has not yet been identified. The aim of this study was therefore to identify a selective hMCT4 inhibitor for use as a pharmacological tool for studying hMCT4. The heterologous expression system of the Xenopus oocyte was used to assess the effects of test compounds on hMCT4, whereupon isobutyrate derivatives, fibrates, and bindarit (2-[(1-benzyl-1H-indazol-3-yl)methoxy]-2-methylpropanoic acid) were demonstrated to exhibit selective inhibitory effects against this transporter. It is suggested that the structure formed from the joining of an isobutyrate moiety and two aromatic rings by appropriate linkers is important for acquiring the selective hMCT4-inhibiting activity. These findings provide novel insights into the ligand recognition of hMCT4, and contribute to the development of novel anticancer agents. (C) 2017 Published by Elsevier Inc.
Rights: ©2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 license
Type: article (author version)
Appears in Collections:薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 小林 正紀

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