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Identification of a selective inhibitor of human monocarboxylate transporter 4
Yuya Futagi1, Masaki Kobayashi2, Katsuya Narumi3
1Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan; Research Fellow of the Japan Society for the Promotion of Science (JSPS), 5-3-1 Kojimachi, Chiyoda-ku, Tokyo 102-0083, Japan.
Abstract:
The human monocarboxylate transporters (hMCTs/SLC16As) mediate the uptake of various monocarboxylates. 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 l-lactate across the plasma membrane. Since hMCT4 is involved in pH regulation and the transport of l-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.
Insights
Researchers identified selective inhibitors for human monocarboxylate transporter 4 (hMCT4), crucial for cancer cell metabolism. This discovery advances the development of targeted anticancer agents by providing a specific pharmacological tool for hMCT4 research.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Human monocarboxylate transporters (hMCTs/SLC16As) facilitate monocarboxylate uptake.
- hMCT4 is upregulated in cancer under hypoxia, transporting l-lactate and influencing pH.
- Targeting hMCT4 offers a potential anticancer strategy, but selective inhibitors are lacking.
Purpose of the Study:
- To identify selective inhibitors of hMCT4.
- To develop a pharmacological tool for studying hMCT4 function.
- To explore the structural basis for hMCT4 ligand recognition.
Main Methods:
- Utilized a Xenopus oocyte heterologous expression system.
- Assessed the inhibitory effects of various compounds on hMCT4.
- Analyzed structure-activity relationships for selective inhibition.
Main Results:
- Identified isobutyrate derivatives, fibrates, and bindarit as selective hMCT4 inhibitors.
- Demonstrated that specific structural features (isobutyrate moiety, aromatic rings, linkers) are key for selective activity.
- Provided novel insights into hMCT4 ligand binding.
Conclusions:
- Isobutyrate derivatives, fibrates, and bindarit are selective hMCT4 inhibitors.
- Structural insights guide the design of future hMCT4-targeting drugs.
- These findings contribute to the development of novel anticancer therapeutics.