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酸素センサー分子Keap-1の活性阻害薬の探索:酸化ストレスの薬物制御

Research Project

Project/Area Number 21659213
Research Category

Grant-in-Aid for Challenging Exploratory Research

Allocation TypeSingle-year Grants
Research Field Kidney internal medicine
Research InstitutionTohoku University

Principal Investigator

宮田 敏男  Tohoku University, 大学院・医学系研究科, 教授 (10222332)

Project Period (FY) 2009
Project Status Completed (Fiscal Year 2009)
Budget Amount *help
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2009: ¥3,100,000 (Direct Cost: ¥3,100,000)
Keywords酸化ストレス応答 / Nrf2-Keep1相互作用 / keep1阻害剤 / X線結晶解析情報 / レポーターアッセイ / SBDD / ジメチルマレイン酸 / edaravone
Research Abstract

その下流に多くの抗酸化ストレス遺伝子を擁するNrf2は異物代謝・酸化ストレス応答の鍵となる転写活性化因子であり、Keap1によって負の制御を受けている。本研究はKeap1に結合し、Nrf2-Keap1相互作用を阻害することでNrf2の分解を抑制し、Nrf2並びに抗酸化ストレス遺伝子の活性化をもたらす新規低分子化合物をstructure based drug design (SBDD)に基づくvirtual screeningとvitro生物学的評価法により探索して、病態解明のみならず治療コンセプトの検証に用いるための候補化合物の選定を目的とした。
Keap1分子のX線結晶解析情報を基に、その活性調節部位に挿入し活性を阻害する低分子ヒット化合物をSBDDで探索し、該当する化合物から購入あるいは合成できた37化合物を検体とした。化合物のvitro生物学的評価は、Nrf2 locusにLacZをノックインしてNeh2-LacZ融合タンパク質が発現するようになったマウス繊維芽細胞を使用してレポーターアッセイを行い、DEM(ジメチルマレイン酸)を陽性対照として、検体によるβ-galacosidase活性をscreeningした。
結果は、37化合物中、陽性対照のDEMとほぼ匹敵する活性を示す1化合物(TM-8009)が得られ、期初の目標は達成された。また、抗酸化作用等が知られる既存薬や臨床候補化合物のscreeningも行い、edaravoneにも同様の活性があることが確認された。
今後、それらの新たに見出された化合物をリードとして構造最適化を図り、vivoでの治療コンセプトの検証をしたいと考えている。

Report

(1 results)
  • 2009 Annual Research Report
  • Research Products

    (38 results)

All 2010 2009

All Journal Article (20 results) (of which Peer Reviewed: 20 results) Presentation (17 results) Book (1 results)

  • [Journal Article] Prevention and treatment of diabetic nephropathy : new approaches2010

    • Author(s)
      Miyata T, van Ypersele de Strihou C.
    • Journal Title

      Review of Endocrinology (未定, In press)

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A novel inhibitor of plasminogen activator inhibitor-1 provides anti-thrombotic benefits devoid of bleeding effect in non-human primates2010

    • Author(s)
      Izuhara Y, Yamaoka N, Kodama H, Dan T, Takizawa S, Hirayama N, Meguro K, van Yperselede Strihou Charles, Miyata T.
    • Journal Title

      J Cereb Blood Flow Metab 30

      Pages: 904-912

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Enhanced carbonyl stress in a subpopulation of schizophrenia2010

    • Author(s)
      Arai M, Yuzawa H, Nohara I, Ohnishi T, Obata N, Iwayama Y, Haga S, Toyota T, Ujike H, Arai M, Ichikawa T, Nishida A, Tanaka Y, Furukawa A, Aikawa Y, Kuroda O, Niizato K, Izawa R, Nakamura K, Mori N, Matsuzawa D, Hashimoto K, Iyo M, Sora I, Matsushita M, Okazaki Y, Yoshikawa T, Miyata T, Itokawa M.
    • Journal Title

      Arch Gen Psychiatry (未定, In press)

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Effect of edaravone on the estimated glomerular filtration rate (eGFR) in acute ischemic stroke patients with chronic kidney disease2010

    • Author(s)
      Tsukamoto Y, Takizawa S, Takahashi W, Mase H, Miyachi H, Miyata T, Takagi S.
    • Journal Title

      J Stroke Cerebrovasc Dis (未定, In press)

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Relationship of Skin-autofluorescence to Cardiovascular Disease in Japanese Hemodialysis Patients2010

    • Author(s)
      Tanaka K, Katoh T, Asai J, Nemoto F, Suzuki H, Asahi K, Sato K, Sakaue M, Miyata T, Watanabe T.
    • Journal Title

      Ther Apher Dial (未定, In press)

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Body weight control by a high-carbohydrate/low-fat diet slows the progression of diabetic kidney damage in an obese, hypertensive, type 2 diabetic rat model2010

    • Author(s)
      Ohtomo S, Izuhara Y, Nangaku M, Dan T, Ito S, Van Ypersele de Strihou C, Miyata T.
    • Journal Title

      J Obesity (未定, In press)

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Hyperglycaemia-induced impairment of endothelium-dependent vasorelaxation in rat mesenteric arteries is mediated by intracellular methylglyoxal levels in a pathway dependent on oxidative stress2010

    • Author(s)
      Brouwers O, Niessen PM, Haenen G, Miyata T, Brownlee M, Stehouwer CD, De Mey JG, Schalkwijk CG.
    • Journal Title

      Diabetologia 53

      Pages: 989-1000

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Advanced glycation end-products, anti hypertensive treatment and diastolic function in patients with hypertension and diastolic dysfunction2010

    • Author(s)
      Hartog JW, van de Wal RM, Schalkwijk CG, Miyata T, Jaarsma W, Plokker HW, van Wijk LM, Smit AJ, van Veldhuisen DJ, Voors AA.
    • Journal Title

      Eur.J.Heart Failure 12

      Pages: 397-403

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Metallothionein is upregulated by hypoxia and stabilizes hypoxia-inducible factor in the kidney2009

    • Author(s)
      Kojima I, Tanaka T, Inagi R, Nishi H, Aburatani H, Kato H, Miyata T, Fujita T, Nangaku M.
    • Journal Title

      Kidney Int 75

      Pages: 268-277

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Advanced glycation end products in patients with cerebral infarction2009

    • Author(s)
      Ohnuki Y, Nagano R, Takizawa S, Takagi S, Miyata T.
    • Journal Title

      Intern Med 48

      Pages: 587-591

    • NAID

      130000108031

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Translation of basic science into clinical medicine : Novel targetsfor diabetic nephropathy2009

    • Author(s)
      Miyata T, van Ypersele de Strihou C.
    • Journal Title

      Nephrol Dial Transplant 24

      Pages: 1373-1377

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Glyoxalase I overexpression ameliorates renal ischemia-reperfusion injury in rats2009

    • Author(s)
      Kumagai T, Nangaku M, Kojima I, Nagai R, Julie R.Ingelfinger, Miyata T, Fujita T, Inagi R.
    • Journal Title

      Am J Physiol-Renal Physiol 296

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Translational medicine : Novel mechanisms and therapeutic options in diabetic nephropathy2009

    • Author(s)
      Miyata T.
    • Journal Title

      Pol Arch Med Wewn 119

      Pages: 261-264

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Effects of NXY-059 in experimental stroke : an individual animal meta-analysis2009

    • Author(s)
      Bath PM, Gray LJ, Bath AJ, Buchan A, Miyata T, Green AR : NXY-059 Efficacy Meta-analysis in Individual Animals with Stroke Investigators
    • Journal Title

      British J Pharmacology 157

      Pages: 1157-1171

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Very high doses of valsartan provide renoprotection independently of blood pressure in a type 2 diabetic nephropathy rat model2009

    • Author(s)
      Tominaga N, Robert A, Izuhara Y, Ohtomo S, Dan T, Chihara K, Kurokawa K, van Ypersele de Strihou C Miyata T.
    • Journal Title

      Nephrology 14

      Pages: 581-587

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A sartan derivative with a very low angiotensin II receptor affinity ameliorates ischemic cerebral damage2009

    • Author(s)
      Takizawa S, Uesugi T, Nagata E, Takagi S, van Ypersele de Strihou C, Miyata T.
    • Journal Title

      J Cereb Blood Flow Metab 29

      Pages: 1665-1672

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Angiotensin II type 1A receptor deficiency and longevity2009

    • Author(s)
      Nishiyama A, Matsusaka T, Miyata T.
    • Journal Title

      Nephrol Dial Transplant 24

      Pages: 3280-3281

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Methylglyoxal contributes to the development of insulin resistance and salt sensitivity in Sprague Dawley rats2009

    • Author(s)
      Qi G, Mori T, Jiang Y, Hu C, Osaki Y, Yoneki Y, Sun Y, Hosoya T, Kawamata A, Ogawa S, Nakayama M, Miyata T, Ito S.
    • Journal Title

      J Hyperten 27

      Pages: 1664-1671

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Inhibition of prolyl hydroxylase domain-containing protein suppressed 1 ipopolysaccharide-induced TNF-a expression2009

    • Author(s)
      Takeda K, Ichiki T, Narabayashi E, Inanaga K, Miyazaki R, Hashimoto T, Matsuura H, Ikeda J, Miyata T, Sunagawa K.
    • Journal Title

      Arterio Thromb Vas Biol 29

      Pages: 2132-2137

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Diabetic nephropathy : a disorder of oxygen metabolism?2009

    • Author(s)
      Miyata T, van Ypersele de Strihou C.
    • Journal Title

      Nat Rev Nephrol 6

      Pages: 83-95

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Presentation] 糖尿病性腎症と酸素代謝異常2010

    • Author(s)
      宮田敏男
    • Organizer
      レドックス生命科学第170委員会第22回研究会
    • Place of Presentation
      大阪
    • Year and Date
      2010-03-19
    • Related Report
      2009 Annual Research Report
  • [Presentation] RAS阻害薬の臓器保護について2010

    • Author(s)
      宮田敏男
    • Organizer
      苫小牧ラジレス講演会
    • Place of Presentation
      苫小牧
    • Year and Date
      2010-03-11
    • Related Report
      2009 Annual Research Report
  • [Presentation] RAS阻害薬の臓器保護について2010

    • Author(s)
      宮田敏男
    • Organizer
      白石医師会講演会
    • Place of Presentation
      仙台
    • Year and Date
      2010-03-09
    • Related Report
      2009 Annual Research Report
  • [Presentation] 大学からの創薬2010

    • Author(s)
      宮田敏男
    • Organizer
      東北大学国際産学連携シンポジウム
    • Place of Presentation
      東京
    • Year and Date
      2010-02-22
    • Related Report
      2009 Annual Research Report
  • [Presentation] 糖尿病性腎症と酸素代謝異常2010

    • Author(s)
      宮田敏男
    • Organizer
      日本内科学会東北支部・第55回生涯教育講演会
    • Place of Presentation
      仙台
    • Year and Date
      2010-02-20
    • Related Report
      2009 Annual Research Report
  • [Presentation] DRIのポテンシャル-降圧と独立した腎臓保護-2010

    • Author(s)
      宮田敏男
    • Organizer
      DRI FORUM
    • Place of Presentation
      横浜
    • Year and Date
      2010-02-03
    • Related Report
      2009 Annual Research Report
  • [Presentation] Development of novel therapeutic agents for the treatment of renal car diovascular diseases : inhibitors of plasminogen inhibitor 1 and oxygen sensor prolylhydroxylase2009

    • Author(s)
      宮田敏男
    • Organizer
      The 1st International Symposium~Challenge to Medical Innovation~
    • Place of Presentation
      仙台
    • Year and Date
      2009-12-07
    • Related Report
      2009 Annual Research Report
  • [Presentation] RAS阻害薬の臓器保護について2009

    • Author(s)
      宮田敏男
    • Organizer
      Rasilez Expert Meeting in Sapporo
    • Place of Presentation
      札幌
    • Year and Date
      2009-11-28
    • Related Report
      2009 Annual Research Report
  • [Presentation] 増加する腎臓病-如何に早期に診断し治療するか2009

    • Author(s)
      宮田敏男
    • Organizer
      町田RAAフォーラム
    • Place of Presentation
      東京
    • Year and Date
      2009-11-19
    • Related Report
      2009 Annual Research Report
  • [Presentation] 糖尿病性腎症と酸素代謝異常2009

    • Author(s)
      宮田敏男
    • Organizer
      大阪CKDエキスパート会議
    • Place of Presentation
      大阪
    • Year and Date
      2009-11-13
    • Related Report
      2009 Annual Research Report
  • [Presentation] 増加する腎臓病-如何に早期に診断し治療するか2009

    • Author(s)
      宮田敏男
    • Organizer
      福島県白河地区学術講演会
    • Place of Presentation
      福島
    • Year and Date
      2009-10-14
    • Related Report
      2009 Annual Research Report
  • [Presentation] 糖尿病性腎症と酸素代謝異常について2009

    • Author(s)
      宮田敏男
    • Organizer
      第8回秋田県分子病態研究会
    • Place of Presentation
      秋田
    • Year and Date
      2009-10-09
    • Related Report
      2009 Annual Research Report
  • [Presentation] Abnormalities of oxygen metabolism in diabetic nephropathy ; Hypoxia and oxidative stress2009

    • Author(s)
      宮田敏男
    • Organizer
      第21回腎とフリーラジカル研究会
    • Place of Presentation
      岡山
    • Year and Date
      2009-09-26
    • Related Report
      2009 Annual Research Report
  • [Presentation] Advanced glycation, hypoxia, and oxidative stress2009

    • Author(s)
      宮田敏男
    • Organizer
      World Congress of Nephrology
    • Place of Presentation
      Milan, Italy
    • Related Report
      2009 Annual Research Report
  • [Presentation] Interplays among hypoxia, oxidative stress, and advanced glycation?2009

    • Author(s)
      宮田敏男
    • Organizer
      10th International Symposium of the Maillard Reaction
    • Place of Presentation
      Palm Cove, Australia
    • Related Report
      2009 Annual Research Report
  • [Presentation] COUP-TFIIは、Wnt/β-cateninシグナルの下流でPPARγの発現をエピジェネティックに調節することで脂肪細胞分化を制御する2009

    • Author(s)
      岡村将史, 若林賢一, 堤修一, 宮田敏男, 内藤眞, 浜窪隆雄, 伊藤貞嘉, 油谷浩幸, 児玉龍彦, 酒井寿郎
    • Organizer
      第13回日本心血管内分泌代謝学会
    • Place of Presentation
      埼玉
    • Related Report
      2009 Annual Research Report
  • [Presentation] 大学からの創薬の一例-出血性副作用のない経口抗血栓薬(PAI-1阻害薬)2009

    • Author(s)
      宮田敏男
    • Organizer
      第16回理事長ファンドワークショップ
    • Place of Presentation
      岐阜
    • Related Report
      2009 Annual Research Report
  • [Book] Oxidative Stress in Applied Basic Research and Clinical Practice : 'Renal Disorders'2010

    • Author(s)
      宮田敏男, van Ypersele de Strihou C.
    • Publisher
      Springer(印刷中)
    • Related Report
      2009 Annual Research Report

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Published: 2009-04-01   Modified: 2016-04-21  

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