Development of novel drug for bone-related diseases using Pirin inhibitors

• Project/Area Number: 24310167
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Chemical biology
• Research Institution: Keio University
• Principal Investigator: SIMIZU Siro 慶應義塾大学, 理工学部, 准教授 (30312268)
• Co-Investigator(Renkei-kenkyūsha): UMEZAWA Kazuo 愛知医科大学, 医学部, 教授 (70114402)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥18,590,000 (Direct Cost: ¥14,300,000、Indirect Cost: ¥4,290,000); Fiscal Year 2014: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2013: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2012: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000)
• Keywords: 骨関連疾患 / Pirin / 破骨細胞 / 破骨細胞分化 / ケミカルバイオロジー / RANKL / 骨疾患 / 低分子化合物 / 骨粗鬆症 / 骨転移 / 構造活性相関

Outline of Final Research Achievements

The number of bone-related disease patients is increasing in Japan. At present, bisphosphonates are widely used for these diseases, but their severe side effects are impossible to ignore.
We focused on TPh A, a Pirin inhibitor, as a novel drug for such diseases. We assayed many derivatives of TPh A and found that 2 compounds inhibited RANKL-induced osteoclastgenesis on Pirin-independent manner without cytotoxicity. These compounds did not suppress phosphorylation of MAPKs, although its inhibited expression of c-Fos and DC-STAMP. Therefore, it is suggested that the compounds we found might be candidates for drugs of bone-related diseases.

Research Products

• [Journal Article] Inhibition of MMP-2-Mediated Mast Cell Invasion by NF-κB Inhibitor DHMEQ in Mast Cells (2015)
  • Author(s): Noma N, Asagiri M, Takeiri M, Ohmae S, Takemoto K, Iwaisako K, Minato N, Maeda-Yamamoto M, Simizu S, Umezawa K.
  • Journal Title: Int. Arch. Allergy Immunol. Volume: 166 Pages: 84-90
  • Peer Reviewed
• [Journal Article] Pirin regulates the epithelial to mesenchymal transition independently of Bcl3-Slug signaling. (2015)
  • Author(s): Komai, K., Niwa, Y., Sasazawa, Y. & Simizu, S.
  • Journal Title: FEBS Lett. Volume: 589 Issue: 6 Pages: 738-743
  • DOI: 10.1016/j.febslet.2015.01.040
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Conophylline Protects Cells in Cellular Models of Neurodegenerative Diseases by Inducing Mammalian Target of Rapamycin (mTOR)-independent Autophagy (2015)
  • Author(s): Sasazawa Y, Sato N, Umezawa K, Simizu S.
  • Journal Title: J. Biol. Chem. Volume: 290 Issue: 10 Pages: 6168-6178
  • DOI: 10.1074/jbc.m114.606293
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Activation of apoptosis by caspase-3-dependent specific RelB cleavage in anticancer agent-treated cancer cells: involvement of positive feedback mechanism (2015)
  • Author(s): Kuboki M, Ito A, Simizu S, Umezawa K.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 456 Issue: 3 Pages: 810-814
  • DOI: 10.1016/j.bbrc.2014.12.024
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] N-Glycosylation of extracellular matrix protein 1 (ECM1) regulates its secretion, which is unrelated to lipoid proteinosis (2015)
  • Author(s): Uematsu S, Goto Y, Suzuki T, Sasazawa Y, Dohmae N, Simizu S.
  • Journal Title: FEBS Open Bio Volume: 4 Issue: 1 Pages: 879-885
  • DOI: 10.1016/j.fob.2014.10.004
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Isolation of a novel paxilline analog pyrapaxilline from fungus that inhibits LPS-induced NO production (2015)
  • Author(s): Matsui C, Ikeda Y, Iinuma H, Kushida N, Kunisada T, Simizu S, Umezawa K.
  • Journal Title: J. Antibiot. Volume: 67 Issue: 11 Pages: 787-790
  • DOI: 10.1038/ja.2014.63
  • Peer Reviewed
• [Journal Article] N-glycosylation is required for secretion and enzymatic activity of human hyaluronidase1. (2014)
  • Author(s): Goto, Y., Niwa, Y., Suzuki, T., Uematsu, S., Dohmae, N. & Simizu, S.
  • Journal Title: FEBS Open Bio Volume: 4 Issue: 1 Pages: 554-559
  • DOI: 10.1016/j.fob.2014.06.001
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] C-mannosylation of human hyaluronidase 1: Possible roles for secretion and enzymatic activity. (2014)
  • Author(s): Goto, Y., Niwa, Y., Suzuki, T., Dohmae, N., Umezawa, K. & Simizu, S.
  • Journal Title: Int. J. Oncol. Volume: 45 Issue: 1 Pages: 344-350
  • DOI: 10.3892/ijo.2014.2438
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Involvement of conserved tryptophan residues for secretion of TIMP-2 (2014)
  • Author(s): Ukaji, T., Sasazawa, Y., Umezawa, K. & Simizu, S.
  • Journal Title: Oncology Letters Volume: 7 Pages: 631-634
  • Peer Reviewed
• [Journal Article] Practical molecular targets for suppression of metastasis (2013)
  • Author(s): Simizu, S. & Niwa, Y.
  • Journal Title: Forum on Immunopathological Diseases and Therapeutics Volume: 4 Pages: 43-51
  • Peer Reviewed
• [Journal Article] Determination of topological structure of ARL6ip1 in cells: identification of the essential binding region of ARL6ip1 for conophylline (2013)
  • Author(s): Kuroda, M., Funasaki, S., Saitoh, T., Sasazawa, Y., Nishiyama, S., Umezawa, K. & Simizu, S.
  • Journal Title: FEBS Letters Volume: 587 Issue: 22 Pages: 3656-3660
  • DOI: 10.1016/j.febslet.2013.09.017
  • Peer Reviewed
• [Journal Article] Migracins A and B, new inhibitors of cancer cell migration, produced by Streptomyces sp (2013)
  • Author(s): Arai, Y., Iinuma, H., Ikeda, Y., Igarashi, M., Hatano, M., Kinoshita, N., Ukaji, T., Simizu, S. & Umezawa, K
  • Journal Title: The Journal of Antibiotics Volume: (掲載決定) Issue: 4 Pages: 225-230
  • DOI: 10.1038/ja.2012.112
  • NAID: 10031168683
  • Peer Reviewed
• [Journal Article] Inhibition of NO-induced β-cell death by novel NF-κB inhibitor (-)-DHMEQ via activation of Nrf2-ARE pathway (2013)
  • Author(s): Ogasawara, A., Simizu, S., Ito, A., Kawai, T., Saisho, Y., Takei, I. & Umezawa, K
  • Journal Title: Biochemical and Biophysical Research Communications Volume: (掲載決定) Issue: 2 Pages: 181-187
  • DOI: 10.1016/j.bbrc.2013.02.062
  • Peer Reviewed
• [Journal Article] Suppression of cellular invasion by glybenclamide through inhibited secretion of platelet-derived growth factor in ovarian clear cell carcinoma ES-2 cells (2012)
  • Author(s): Yasukagawa, T., Niwa, Y., Simizu, S. & Umezawa, K
  • Journal Title: FEBS Letters Volume: 586 Issue: 10 Pages: 1504-1509
  • DOI: 10.1016/j.febslet.2012.04.007
  • Peer Reviewed
• [Journal Article] Inhibition of lysenin-induced hemolysis by all-E-lutein derived from the plant Dalbergia latifolia (2012)
  • Author(s): Niwa, Y., Matsui, C., Sukumwang, N., Iinuma, H., Ikeda, Y., Koyano, T., Kovitayakorn, T., Simizu, S. & Umezawa, K
  • Journal Title: Planta Medica Volume: 78 Issue: 10 Pages: 957-961
  • DOI: 10.1055/s-0031-1298538
  • Peer Reviewed
• [Journal Article] Determination of cathepsin V activity and intracellular trafficking by N-glycosylation (2012)
  • Author(s): Niwa, Y., Suzuki, T., Dohmae, N., Umezawa, K. & Simizu, S
  • Journal Title: FEBS Letters Volume: 586 Issue: 20 Pages: 3601-3607
  • DOI: 10.1016/j.febslet.2012.08.001
  • Peer Reviewed
• [Presentation] クラビラクトン類縁体の合成 (2015)
  • Author(s): 茂木 拓馬、吉田 圭佑、高尾 賢一、宮嵜 奏、笹澤 有紀子、清水 史郎
  • Organizer: 日本化学会 第95春季年会
  • Place of Presentation: 日本大学（千葉県・船橋市）
  • Year and Date: 2015-03-26 – 2015-03-29
• [Presentation] Identification of a compound that regulates autophagy in cells (2015)
  • Author(s): Siro Simizu
  • Organizer: International Mini Symposium on Chemical Biology of Natural Products
  • Place of Presentation: 慶應義塾大学（神奈川県・横浜市）
  • Year and Date: 2015-03-24
  • Invited
• [Presentation] Pirin downregulates E-cadherin gene expression and contribute to EMT (2014)
  • Author(s): Kuniya Komai, Yuki Niwa, Yukiko Sasazawa, Siro Simizu
  • Organizer: EORTC-NCI-AACR International Symposium on Molecular Targets and Cancer Therapeutics
  • Place of Presentation: Barcelona（Spain）
  • Year and Date: 2014-11-18 – 2014-11-21
• [Presentation] Human DPY19L3 is a C-mannosyltransferase for R-spondin1 and regulates R-spondin1 secretion (2014)
  • Author(s): 丹羽 祐貴、清水 史郎
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Secretion of Extracellular matrix protein 1 is regulated by N-glycosylation (2014)
  • Author(s): 植松 史帆、後藤 祐貴、笹澤 有紀子、清水 史郎
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Pirin regulates EMT by downregulating E-cadherin gene expression (2014)
  • Author(s): 駒井 邦哉、丹羽 祐貴、笹澤 有紀子、清水 史郎
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] N-glycosylation regulates R-spondin1 functions (2014)
  • Author(s): 土屋 みゆ、丹羽 祐貴、清水 史郎
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] C-mannosylationによるR-spondin1の機能制御 (2014)
  • Author(s): 丹羽 祐貴、清水 史郎
  • Organizer: 第23回 日本がん転移学会学術集会・総会
  • Place of Presentation: 金沢市文化ホール（石川県・金沢市）
  • Year and Date: 2014-07-10 – 2014-07-11
• [Presentation] N-linked glycan which attached Asn354 regulate secretion of Extracellular matrix protein 1 (2014)
  • Author(s): Shiho Uematsu, Yuki Goto, Takehiro Suzuki, Yukiko Sasazawa, Naoshi Dohmae, Siro Simizu
  • Organizer: 15th International Biennial Congress of the Metastasis Research Society
  • Place of Presentation: Heidelberg（Germany）
  • Year and Date: 2014-06-28 – 2014-07-01
• [Presentation] R-spondin1 functions are regulated by N-glycosylation (2014)
  • Author(s): Miyu Tsuchiya, Yuki Niwa, Siro Simizu
  • Organizer: 15th International Biennial Congress of the Metastasis Research Society
  • Place of Presentation: Heidelberg（Germany）
  • Year and Date: 2014-06-28 – 2014-07-01
• [Presentation] N型糖鎖修飾がHYAL1機能に与える影響 (2014)
  • Author(s): 後藤 祐貴、丹羽 祐貴、堂前 直、清水 史郎
  • Organizer: 日本がん分子標的治療学会 第18回学術集会
  • Place of Presentation: 仙台市情報・産業プラザ（宮城県・仙台市）
  • Year and Date: 2014-06-25 – 2014-06-27
• [Presentation] Conophyllineの抗ハンチントン病作用 (2014)
  • Author(s): 佐藤 夏実、笹澤 有紀子、梅澤 一夫、清水 史郎
  • Organizer: 日本ケミカルバイオロジー学会 第9回年会
  • Place of Presentation: 大阪大学（大阪府・豊中市）
  • Year and Date: 2014-06-11 – 2014-06-13
• [Presentation] 破骨細胞分化阻害剤の作用機構解析 (2014)
  • Author(s): 笹澤 有紀子、森下 佳典、杉野 公美、川谷 誠、長田 裕之、清水 史郎
  • Organizer: 日本ケミカルバイオロジー学会 第9回年会
  • Place of Presentation: 大阪大学（大阪府・豊中市）
  • Year and Date: 2014-06-11 – 2014-06-13
• [Presentation] Regulation of Wnt signaling by glycosylation (2014)
  • Author(s): Siro Simizu
  • Organizer: Universiti Sains Malaysia Public Lecture
  • Place of Presentation: Penang, Malaysia
  • Invited
• [Presentation] Hyaluronidase1 activity and secretion are regulated by C-mannosylation (2013)
  • Author(s): Simizu, S., et al.
  • Organizer: 9th AACRJCA Joint Conference
  • Place of Presentation: Hyatt Regency Maui (アメリカ)
  • Year and Date: 2013-02-24
• [Presentation] Involvement of glycosylation in hyaluronidase1 functions (2013)
  • Author(s): Siro Simizu, Yuki Goto, Yuki Niwa
  • Organizer: 9th International Conference on Hyaluronan
  • Place of Presentation: Oklahoma City, OK; USA
  • Invited
• [Presentation] NF-kappa B阻害剤(-)-DHMEQはMMP-2依存性のマスト細胞浸潤を抑制する (2013)
  • Author(s): 野間 成人、清水 史郎、梅澤 一夫
  • Organizer: 日本がん分子標的治療学会 第16回学術集会
  • Place of Presentation: 京都
• [Presentation] Conophylline標的タンパク質ARL6ip1の小胞体におけるトポロジー解析 (2013)
  • Author(s): 黒田 将広、宇梶 珠未、笹澤 有紀子、清水 史郎
  • Organizer: 日本ケミカルバイオロジー学会 第8回年会
  • Place of Presentation: 東京
• [Presentation] Conophyllineによるオートファジー誘導 (2013)
  • Author(s): 笹澤 有紀子、梅澤 一夫、清水 史郎
  • Organizer: 日本ケミカルバイオロジー学会 第8回年会
  • Place of Presentation: 東京
• [Presentation] オートファジーを制御する新規化合物の探索 (2013)
  • Author(s): 田中 敦史、近藤 恭光、清水 史郎、斎藤 臣雄、長田 裕之、野田 健司、吉森 保
  • Organizer: 第65回 日本細胞生物学会大会
  • Place of Presentation: 名古屋
• [Presentation] R-spondin1の機能に与えるC-mannosylationの役割 (2013)
  • Author(s): 丹羽 祐貴、清水 史郎
  • Organizer: 第22回 日本がん転移学会学術集会・総会
  • Place of Presentation: 松本
• [Presentation] 細胞内ロジスティクス研究におけるケミカルバイオロジーの役割 (2013)
  • Author(s): 清水 史郎
  • Organizer: 新学術領域研究「細胞内ロジスティクス」終了シンポジウム
  • Place of Presentation: 淡路島
• [Presentation] Induction of NF-kappa B and induction of selective apoptosis by novel alkylglutarimide compounds in adult T-cell leukemia cells (2013)
  • Author(s): 宇梶 珠未、竹入 雅敏、伊藤 あゆみ、清水 史郎、梅澤 一夫
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] Role of glycosylation on Hyaluronidase1 functions (2013)
  • Author(s): 後藤 祐貴、丹羽 祐貴、清水 史郎
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] Regulation of R-spondin1 secretion by C-mannosylation (2013)
  • Author(s): 丹羽 祐貴、清水 史郎
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] Secretion of R-spondin1 is regulated by C-mannosylation (2013)
  • Author(s): Yuki Niwa, Siro Simizu
  • Organizer: AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics
  • Place of Presentation: Boston, MA; USA
• [Presentation] Neuroprotective effect of conophylline in cellular model of Parkinson’s disease (2013)
  • Author(s): Yukiko Sasazawa, Kazuo Umezawa, Siro Simizu
  • Organizer: International Symposium on Mitochondria 2013
  • Place of Presentation: 東京
• [Presentation] TPh A 誘導体の破骨細胞分化に及ぼす影響と構造活性相関解析 (2013)
  • Author(s): 森下 佳典、笹澤 有紀子、杉野 公美、川谷 誠、長田 裕之、清水 史郎
  • Organizer: 日本農芸化学会関東支部会2013年度大会
  • Place of Presentation: 横浜
• [Presentation] 海洋産マクロリドBiselyngbyaside類の構造と生物活性 (2013)
  • Author(s): 森田 真布、大野 修、矢守 隆夫、丹羽 祐貴、清水 史郎、末永 聖武
  • Organizer: 日本農芸化学会関東支部会2013年度大会
  • Place of Presentation: 横浜
• [Presentation] conophyllineによる神経保護効果の解 (2013)
  • Author(s): 笹澤 有紀子、梅澤 一夫、清水 史郎
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸
• [Presentation] Regulation of hyaluronidasel enzymatic activity by C-mannosylation (2012)
  • Author(s): Goto, Y., et al.
  • Organizer: EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics
  • Place of Presentation: Convention Centre Dublin (アイルランド)
  • Year and Date: 2012-11-09
• [Presentation] Induction of RelB degradation and apoptosis in adult T-cell leukemia cells by DTCM-glutarimide (2012)
  • Author(s): 伊藤あゆみ、他
  • Organizer: 第71回 日本癌学会学術総会
  • Place of Presentation: ロイトン札幌、他(北海道)
  • Year and Date: 2012-09-21
• [Presentation] Role of C-mannosylation on hyaluronidasel functions (2012)
  • Author(s): 後藤祐貴、他
  • Organizer: 第71回 日本癌学会学術総会
  • Place of Presentation: ロイトン札幌、他(北海道)
  • Year and Date: 2012-09-19
• [Presentation] N-glycosylation regulates cathepsin L2 functions (2012)
  • Author(s): Niwa, Y., et al.
  • Organizer: The 14th International Biennial Congress of the Metastasis Research Society
  • Place of Presentation: Brisbane Convention Centre & Exhibition Centre (オーストラリア)
  • Year and Date: 2012-09-04
• [Presentation] カテプシンL2の機能に与えるN-glycosylationの役割 (2012)
  • Author(s): 丹羽祐貴、他
  • Organizer: 第21回 日本がん転移学会学術集会・総会
  • Place of Presentation: オリエンタルホテル広島(広島県)
  • Year and Date: 2012-07-13
• [Presentation] がん分子標的研究の今昔 (2012)
  • Author(s): 清水史郎
  • Organizer: 理研セミナー
  • Place of Presentation: 理化学研究所(埼玉県)(招待講演)
  • Year and Date: 2012-07-13
• [Presentation] 植物性アルカロイドconophyllineによる癌細胞薬剤耐性の軽減と標的タンパク質の結合解析 (2012)
  • Author(s): 舟崎慎太郎、他
  • Organizer: 日本がん分子・標的治療学会 第16回学術集会
  • Place of Presentation: 西日本総合展示場 (福岡県)
  • Year and Date: 2012-06-28
• [Presentation] 免疫抑制剤デオキシスパーガリンの標的分子の探索 (2012)
  • Author(s): 村橋将崇、他
  • Organizer: 日本ケミカルバイオロジー学会 第7回年会
  • Place of Presentation: 京都大学(京都府)
  • Year and Date: 2012-06-07
• [Remarks] 研究室ホームページ
  • URL: http://www.applc.keio.ac.jp/~simizu/
• [Remarks] 研究室ホームページ
  • URL: http://www.applc.keio.ac.jp/~simizu/
• [Remarks]
  • URL: http://www.applc.keio.ac.jp/~simizu/