Development of SPAK kinase inhibitors
Project/Area Number |
25670406
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Research Category |
Grant-in-Aid for Challenging Exploratory Research
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Allocation Type | Multi-year Fund |
Research Field |
Kidney internal medicine
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Research Institution | Tokyo Medical and Dental University |
Principal Investigator |
UCHIDA SHINICHI 東京医科歯科大学, 医歯(薬)学総合研究科, 教授 (50262184)
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Project Period (FY) |
2013-04-01 – 2015-03-31
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Project Status |
Completed (Fiscal Year 2014)
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Budget Amount *help |
¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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Keywords | 高血圧 / 創薬 / キナーゼ / ケミカルライブラリー / キナーゼ阻害薬 |
Outline of Final Research Achievements |
WNK- STE20/SPS1-related proline-alanine-rich protein kinase (SPAK)-SLC12a transporters cascade regulates blood pressure through NaCl reabsorption in kidney and vasoconstriction. Therefore, drugs that inhibit this signal cascade could become new antihypertensive drugs that have dual effects as a diuretic and vasodilator. We sought to discover SPAK kinase inhibitors by screening chemical compounds and existing drugs. We developed a new screening system using enzyme-linked immunosorbent assay (ELISA) and screened over 20,000 small-molecule compounds. As a result of this screening effort, we discovered one small-molecule compound and Closantel, an antiparasitic agent, which inhibited SPAK-regulated NCC and NKCC1 phosphorylation and activation not only in vitro but also in cultured cell lines and in mice.
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Report
(3 results)
Research Products
(24 results)
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[Journal Article] Kelch-Like Protein 2 Mediates Angiotensin II-With No Lysine 3 Signaling in the Regulation of Vascular Tonus2015
Author(s)
Zeniya M, Morimoto N, Takahashi D, Mori Y, Mori T, Ando F, Araki Y, Yoshizaki Y, Inoue Y, Isobe K, Nomura N, Oi K, Nishida H, Sasaki S, Sohara E, Rai T, Uchida S
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Journal Title
J Am Soc Nephrol
Volume: 26
Issue: 9
Pages: 2129-2138
DOI
Related Report
Peer Reviewed
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[Journal Article] Discovery of Novel SPAK Inhibitors That Block WNK Kinase Signaling to Cation Chloride Transporters2014
Author(s)
Kikuchi E, Mori T, Zeniya M, Isobe K, Ishigami-Yuasa M, Fujii S, Kagechika H, Ishihara T, Mizushima T, Sasaki S, Sohara E, Rai T, Uchida S
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Journal Title
J Am Soc Nephrol
Volume: 26
Issue: 7
Pages: 1525-1536
DOI
Related Report
Peer Reviewed
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[Journal Article] Aberrant Glycosylation and Localization of Polycystin-1 Cause Polycystic Kidney in an AQP11 Knockout Model.2014
Author(s)
Inoue Y, Sohara E, Kobayashi K, Chiga M, Rai T, Ishibashi K, Horie S, Su X, Zhou J, Sasaki S, Uchida S.
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Journal Title
J Am Soc Nephrol.
Volume: 25
Issue: 12
Pages: 2789-2799
DOI
Related Report
Peer Reviewed
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[Journal Article] Impaired degradation of WNK1 and WNK4 kinases causes PHAII in mutant KLHL3 knock-in mice2014
Author(s)
Susa K, Sohara E, Rai T, Zeniya M, Mori Y, Mori T, Chiga M, Nomura N, Nishida H, Takahashi D, Isobe K, Inoue Y, Takeishi K, Takeda N, Sasaki S, Uchida S
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Journal Title
Hum Mol Genet
Volume: 23 (19)
Issue: 19
Pages: 5052-60
DOI
Related Report
Peer Reviewed
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[Journal Article] Development of enzyme-linked immunosorbent assays for urinary thiazide-sensitive Na-Cl cotransporter (NCC) measurement.2013
Author(s)
Isobe K, Mori T, Asano T, Kawaguchi H, Nonoyama S, Kumagai N, Kamada F, Morimoto T, Hayashi M, Sohara E, Rai T, Sasaki S, Uchida S.
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Journal Title
Am J Physiol Renal Physiol.
Volume: 305
Related Report
Peer Reviewed
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[Journal Article] Dietary salt intake regulates WNK3-SPAK-NKCC1 phosphorylation cascade in mouse aorta through angiotensin II2013
Author(s)
Zeniya M, Sohara E, Kita S, Iwamoto T, Susa K, Mori T, Oi K, Chiga M, Takahashi D, Yang SS, Lin SH, Rai T, Sasaki S, Uchida S
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Journal Title
Hypertension
Volume: 62(5)
Issue: 5
Pages: 872-8
DOI
Related Report
Peer Reviewed
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[Journal Article] Chemical library screening for WNK signalling inhibitors using fluorescence correlation spectroscopy.2013
Author(s)
Mori, T.; Kikuchi, E.; Watanabe, Y.; Fujii, S.; Ishigami-Yuasa, M.; Kagechika, H.; Sohara, E.; Rai, T.; Sasaki, S.; Uchida, S.
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Journal Title
Biochem. J.
Volume: 455
Issue: 3
Pages: 339-345
DOI
Related Report
Peer Reviewed
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[Journal Article] Phosphorylation regulates NCC stability and transporter activity in vivo.2013
Author(s)
Yang SS, Fang YW, Tseng MH, Chu PY, Yu IS, Wu HC, Lin SW, Chau T, Uchida S, Sasaki S, Lin YF, Sytwu HK, Lin SH.
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Journal Title
J Am Soc Nephrol.
Volume: 24
Issue: 10
Pages: 1587-97
DOI
Related Report
Peer Reviewed
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[Presentation] Impaired KLHL3-mediated ubiquitination of WNK4 activates OSR1 and SPAK kinases-NaCl cotransporter (NCC) signaling and causes hypertension.2013
Author(s)
Wakabayashi M, Mori T, Isobe K, Sohara E, Susa K, Araki Y, Chiga M, Kikuchi E, Nomura N, Mori Y, Rai T, Sasaki S, Uchida S.
Organizer
The 46th Annual meeting of American Society of Nephrology
Place of Presentation
アトランタ, アメリカ合衆国
Related Report
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[Presentation] KLHL2 interacts with and ubiquitinates WNK kinases.2013
Author(s)
Takahashi D, Mori T, Wakabayashi M, Mori Y, Susa K, Zeniya M, Sohara E, Rai T, Sasaki S, Uchida S.
Organizer
The 46th Annual meeting of American Society of Nephrology
Place of Presentation
アトランタ, アメリカ合衆国
Related Report
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[Presentation] WNK3 Regulates Blood Pressure Through the Regulation of Vascular OSR1/SPAK-NKCC1 Phosphorylation Cascade.2013
Author(s)
Zeniya M, Sohara E, Kita S, Iwamoto T, Susa K, Mori T, Oi K, Chiga M, Takahashi D, Yang SS, Lin SH, Rai T, Sasaki S, Uchida S.
Organizer
The 46th Annual meeting of American Society of Nephrology
Place of Presentation
アトランタ, アメリカ合衆国
Related Report
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