Development of protein knockdown technology to degrade pathogenic proteins

• Project/Area Number: 23659048
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Biological pharmacy
• Research Institution: National Institute of Health Sciences
• Principal Investigator: NAITO Mikihiko 国立医薬品食品衛生研究所, 機能生化学部, 部長 (00198011)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2011: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: ユビキチン / プロテアソーム / プロテインノックダウン / cIAP1 / ネクローシス

Research Abstract

We initially developed SNIPER-2 that degrades the target protein CRABP2 and the ubiquitin ligase cIAP1. By chemical modification, we successfully developed SNIPER-4 that selectively degrades the target protein. We also developed SNIPER(ER) that target estrogen receptor-alpha (Erα) for degradation, and found that the SNIPER(ER) induces necrosis in breast cancer cells after the degradation of Erα.

Research Products

• [Journal Article] Design and synthesis of estrogen receptor degradation inducer based on a protein knockdown strategy (2012)
  • Author(s): Demizu, Y., Okuhira, K., Motoi, H., Ohno, A., Shoda, T., Fukuhara, K., Okuda, H., Naito, M. & Kurihara, M.
  • Journal Title: Bioorg Med Chem Lett Volume: 22 Pages: 1793-1796
• [Journal Article] Double protein knockdown of cIAP1 and CRABP-II using a hybrid molecule consisting of ATRA and IAPs antagonist (2012)
  • Author(s): Itoh, Y., Ishikawa, M., Kitaguchi, R., Okuhira, K., Naito, M. & Hashimoto, Y.
  • Journal Title: Bioorg Med Chem Lett Volume: 22 Pages: 4453-4457
• [Journal Article] Double protein knockdown of cIAP1 and CRABP-II using a hybrid molecule consisting of ATRA and IAPs antagonist (2012)
  • Author(s): Y. Itoh, M. Ishikawa, R.Kitaguchi, K.Okuhira, M.Naito, Y.Hashimoto
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 22 Issue: 13 Pages: 4453-4457
  • DOI: 10.1016/j.bmcl.2012.04.134
  • Peer Reviewed
• [Journal Article] Design and synthesis of estrogen receptor degradation inducer based on a protein knockdown strategy (2012)
  • Author(s): Y. Demizu, K. Okuhira, H. Motoi, A. Ohno, T. Shoda, K. Fukuhara, H. Okuda, M. Naito, M. Kurihara
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 22 Issue: 4 Pages: 1793-1796
  • DOI: 10.1016/j.bmcl.2011.11.086
  • Peer Reviewed
• [Journal Article] Specific degradation of CRABP-II via cIAP1-mediated ubiquitylation induced by hybrid molecules that crosslink cIAP1 and the target protein (2011)
  • Author(s): Okuhira, K., Ohoka, N., Sai, K., Nishimaki-Mogami, T., Itoh, Y., Ishikawa, M., Hashimoto, Y. & Naito, M.
  • Journal Title: FEBS Lett Volume: 585 Pages: 1147-1152
• [Journal Article] Design, synthesis and biological evaluation of nuclear receptor-degradation inducers. (2011)
  • Author(s): Itoh, Y., Kitaguchi, R., Ishikawa, M., Naito, M. & Hashimoto, Y.
  • Journal Title: Bioorg Med Chem Volume: 19 Pages: 6768-6778
• [Journal Article] Development of target protein-selective degradation inducer for protein knockdown (2011)
  • Author(s): Itoh, Y., Ishikawa, M., Kitaguchi, R., Sato, S., Naito, M. & Hashimoto, Y.
  • Journal Title: Bioorg Med Chem Volume: 19 Pages: 3229-3241
• [Journal Article] Specific degradation of CRABP-II via cIAP1-mediatd ubiquitylation induced by hybrid molecules that crosslink cIAP1 and the target protein (2011)
  • Author(s): K. Okuhira, N. Ohoka, K. Sai, T. Nishimaki-Mogami, Y. Itoh, M. Ishikawa, Y. Hashimoto, M. Naito
  • Journal Title: FEBS Lett. Volume: 585 Issue: 8 Pages: 1147-1152
  • DOI: 10.1016/j.febslet.2011.03.019
  • Peer Reviewed
• [Journal Article] Development oftarget protein-selective degradation inducerfor protein knockdown (2011)
  • Author(s): Y. Itoh, M. Ishikawa, R. Kitaguchi, S. Sato, M. Naito, Y. Hashimoto
  • Journal Title: Bioorg. Med. Chem Volume: 19 Issue: 10 Pages: 3229-3241
  • DOI: 10.1016/j.bmc.2011.03.057
  • Peer Reviewed
• [Presentation] 細胞内に局在するタンパク質を標的としたプロテインノックダウン技術の評価 (2013)
  • Author(s): 奥平桂一郎,大岡伸通,最上(西巻)知子,伊藤幸裕,石川稔,橋本祐一,内藤幹彦
  • Organizer: 日本薬学会第133年会
  • Place of Presentation: 横浜
• [Presentation] Development of SNIPER(ER) that induces estrogen receptor degradation followed by rapid cell death in breast cancer cells (2013)
  • Author(s): Okuhira, K., Demizu, Y., Ohoka, N., Shibata, N., Hattori, T., Nishimaki-Mogami, T., Kurihara, M., Okuda, H., Naito, M.
  • Organizer: Ninth AACR-Japanese Cancer Association Joint Conference: Breakthroughs in Basic and Translational Cancer Research
  • Place of Presentation: ラハイナ市、米国
• [Presentation] Development of SNIPER(ER) that induces estrogen receptor degradation followed by rapid cell death in breast cancer cells (2013)
  • Author(s): 奥平桂一郎
  • Organizer: Ninth AACR-Japanese Cancer Association Joint Conference: Breakthroughs in Basic and Translational Cancer Research
  • Place of Presentation: Lahaina, USA
• [Presentation] 細胞内に局在するタンパク質を標的としたプロテインノックダウン技術の評価 (2013)
  • Author(s): 奥平桂一郎
  • Organizer: 日本薬学会第133年会
  • Place of Presentation: 横浜市
• [Presentation] 神経変性疾患原因タンパク質分解誘導剤の創製研究 (2013)
  • Author(s): 友重秀介
  • Organizer: 日本薬学会第133年会
  • Place of Presentation: 横浜市
• [Presentation] タンパク質ノックダウン法を利用した新治療戦略と低分子の標的タンパク質同定法 (2013)
  • Author(s): 石川稔
  • Organizer: 日本ケミカルバイオロジー学会 第七回年会
  • Place of Presentation: 京都市
• [Presentation] 細胞膜透過性蛍光NTAの設計・合成 (2013)
  • Author(s): 加藤雅士
  • Organizer: 日本薬学会第133年会
  • Place of Presentation: 横浜市
• [Presentation] 乳癌におけるエストロゲンレセプターの分解を誘導する分子SNIPER(ER)の開発 (2012)
  • Author(s): 奥平桂一郎, 出水庸介, 大岡伸通, 柴田識人, 服部隆行, 最上(西巻)知子, 奥田晴宏, 栗原正明, 内藤幹彦
  • Organizer: 第16回日本がん分子標的治療学会
  • Place of Presentation: 北九州市
• [Presentation] Development of small molecules that induce IAP-mediated ubiquitylation and proteasomal degradation of target proteins in a specific manner (2012)
  • Author(s): Naito, M., Okuhira, K., Demizu, Y., Itoh, Y., Ishikawa, M., Ohoka, N., Shibata, N., Hattori, T., Nishimaki-Mogami, T., Kurihara, M., Hashimoto, Y.
  • Organizer: Cell Symposia: Genetics and Chemistry Sharing a Language of Discovery
  • Place of Presentation: ボストン市、米国
• [Presentation] Development of small molecules that induce IAP-mediated ubiquitylation and proteasomal degradation of target proteins (2012)
  • Author(s): Naito, M., Okuhira, K., Ohoka, N., Shibata, N., Hattori, T., Itoh, Y., Ishikawa, M., Hashimoto, Y.
  • Organizer: The 6th International Conference SUMO, Ubiquitin, UBL Proteins: Implications for Human Diseases
  • Place of Presentation: ヒューストン市、米国
• [Presentation] M.:Development of SNIPER(ER) that induces estrogen receptor degradation (2012)
  • Author(s): Okuhira, K., Demizu, Y., Ohoka, N., Shibata, N., Hattori, T., Nishimaki-Mogami, T., Kurihara, M., Okuda, H., Naito, M.
  • Organizer: The 6th International Conference SUMO, Ubiquitin, UBL Proteins: Implications for Human Diseases
  • Place of Presentation: ヒューストン市、米国
• [Presentation] Degradation of estrogen receptor induced by a small hybrid molecule SNIPER(ER) (2012)
  • Author(s): 奥平桂一郎、出水庸介、大岡伸通、柴田識人、服部隆行、最上(西巻)知子、栗原正明、奥田晴宏、内藤幹彦
  • Organizer: The 16th JFCR-ISCC
  • Place of Presentation: 東京
• [Presentation] Development of small molecules that induce IAP-mediated ubiquitylation and proteasomal degradation of target proteins in a specific manner (2012)
  • Author(s): 内藤幹彦
  • Organizer: Cell Symposia: Genetics and Chemistry Sharing a Language of Discovery
  • Place of Presentation: Boston, USA
• [Presentation] Development of small molecules that induce IAP-mediated ubiquitylation and proteasomal degradation of target proteins (2012)
  • Author(s): Naito, M., Okuhira, K., Ohoka, N., Shibata, N., Hattori, T., Itoh, Y., Ishikawa, M., Hashimoto, Y.
  • Organizer: The 6th International Conference SUMO, Ubiquitin, UBL Proteins: Implications for Human Diseases
  • Place of Presentation: Houston
• [Presentation] Development of SNIPER(ER) that induces estrogen receptor degradation (2012)
  • Author(s): Okuhira, K., Demizu, Y., Ohoka, N., Shibata, N., Hattori, T., Nishimaki-Mogami, T., Kurihara, M., Okuda, H., Naito, M.
  • Organizer: The 6th International Conference SUMO, Ubiquitin, UBL Proteins: Implications for Human Diseases
  • Place of Presentation: Houston
• [Presentation] プロテインノックダウン法によるエストロゲンレセプターの分解 (2012)
  • Author(s): 奥平 桂一郎, 出水 庸介, 大岡 伸通, 柴田 識人, 服部 隆行, 最上（西巻） 知子, 栗原 正明, 奥田 晴宏, 内藤 幹彦
  • Organizer: 日本薬学会第132年会
  • Place of Presentation: 札幌
• [Presentation] プロテインノックダウン法を利用したエストロゲン受容体分解誘導剤の開発 (2012)
  • Author(s): 元井 宏美, 出水 庸介, 佐藤 由紀子, 奥平 桂一郎, 内藤 幹彦, 栗原 正明
  • Organizer: 日本薬学会第132年会
  • Place of Presentation: 札幌
• [Presentation] 細胞内に局在するタンパク質を標的としたプロテインノックダウン技術の検討 (2011)
  • Author(s): 奥平桂一郎、大岡伸通、最上（西巻）知子、伊藤幸裕、石川稔、橋本祐一、内藤幹彦
  • Organizer: 第15回日本がん分子標的治療学会
  • Place of Presentation: 東京
• [Presentation] 抗がん剤、がん分子標的治療薬の作用機序と薬剤耐性の分子機構 (2011)
  • Author(s): 内藤幹彦
  • Organizer: 第55回日本薬学会関東支部大会(招待講演)
  • Place of Presentation: 船橋
• [Presentation] プロテインノックダウン法によるエストロゲン受容体の分解 (2011)
  • Author(s): 奥平桂一郎、出水庸介、大岡伸通、柴田識人、服部隆行、最上（西巻）知子、栗原正明、奥田晴宏、内藤幹彦
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] Protein Knockdown: Selective Degradation of Target Proteins in Cells Using Methyl Bestatin-ligand Hybrid Molecules (2011)
  • Author(s): Minoru Ishikawa, Yukihiro Itoh, Risa Kitaguchi, Shinichi Sato, Mikihiko Naito, and Yuichi Hashimoto
  • Organizer: 8th AFMC International Medicinal Chemistry Symposium
  • Place of Presentation: 東京
• [Presentation] Design and Synthesis of ER Degradation Inducer for Protein Knockdown Strategy (2011)
  • Author(s): Yosuke Demizu, Hiromi Motoi, Keiichiro Okuhira, Kiyoshi Fukuhara, Haruhiro Okuda, Mikihiko Naito, and Masaaki Kurihara
  • Organizer: 8th AFMC International Medicinal Chemistry Symposium
  • Place of Presentation: 東京
• [Remarks]
  • URL: http://www.nihs.go.jp/dfbg/frame.html
• [Remarks] 国立医薬品食品衛生研究所 機能生化学部 ホームページ
  • URL: http://www.nihs.go.jp/dfbg/frame.html
• [Remarks]
  • URL: http://www.nihs.go.jp/dfbg/frame.html
• [Patent(Industrial Property Rights)] アポトーシス阻害タンパク質リガンド－エストロゲン受容体リガンドハイブリッド化合物並びにそれを利用したエストロゲン受容体分解誘導剤及び乳癌、子宮頚癌又は卵巣癌の予防及び治療剤 (2011)
  • Inventor(s): 内藤幹彦、奥平桂一郎、出水庸介、栗原正明
  • Industrial Property Rights Holder: 内藤幹彦、奥平桂一郎、出水庸介、栗原正明
  • Industrial Property Number: 2011-195081
  • Filing Date: 2011