Development of protein knockdown technology to degrade pathogenic proteins

2012 Fiscal Year Final Research Report

• 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
• 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] 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
• [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
  • Year and Date: 20130300
• [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
  • Year and Date: 20130200
• [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
  • Year and Date: 20120600
• [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
  • Year and Date: 20120500
• [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
  • Year and Date: 20120200
• [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
  • Year and Date: 20120200
• [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
  • Year and Date: 20120100
• [Remarks]
  • URL: http://www.nihs.go.jp/dfbg/frame.html