Development of estrogen receptor degrader and analysis of drug-induced cell death mechanism for breast cancer therapy

• Project/Area Number: 25430164
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: The University of Tokushima (2014-2015); National Institute of Health Sciences (2013)
• Principal Investigator: OKUHIRA Keiichiro 徳島大学, 大学院医歯薬学研究部, 准教授 (10425671)
• Co-Investigator(Renkei-kenkyūsha): DEMIZU Yosuke 国立医薬品食品研究所, 有機化学部, 室長 (90389180)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); 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)
• Keywords: 乳癌 / エストロゲン受容体 / エストロゲンレセプター

Outline of Final Research Achievements

Recently, we have developed a hybrid small molecule named SNIPER(ER) (Specific and Non-genetic IAP-dependent Protein Eraser for Estrogen Receptor) that induces degradation of estrogen receptor alpha (ERa) proteins via ubiquitin-proteasome system. In this study, we revealed that SNIPER(ER) induces ROS production after the ERa degradation and caused necrotic cell death of MCF-7 cells, implying a therapeutic potential of SNIPER(ER) as a lead for the treatment of ERa-positive breast cancers.

Research Products

• [Journal Article] Induction of proteasomal degradation of ERα and subsequent cell death in breast cancer cells (2016)
  • Author(s): K. Okuhira, Y. Demizu, T. Hattori, N. Ohoka, N. Shibata, T. Nishimaki-Mogami, H. Okuda, M. Kurihara, M. Naito*
  • Journal Title: Methods Mol. Biol. Volume: 1366 Pages: 549-560
  • DOI: 10.1007/978-1-4939-3127-9_42
  • ISBN: 9781493931262, 9781493931279
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Structural development of stabilized helical peptides as inhibitors of estrogen receptor (ER)-mediated transcription (2015)
  • Author(s): Y. Demizu*, T. Misawa, T. Nagakubo, Y. Kanda, K. Okuhira, Y. Sekino, M. Naito, M. Kurihara*
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 23 Issue: 15 Pages: 4132-4138
  • DOI: 10.1016/j.bmc.2015.06.067
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Synthesis and evaluation of tamoxifen derivatives with a long alkyl side chain as selective estrogen receptor down-regulators (2015)
  • Author(s): T. Shoda,* M. Kato, T. Fujisato, K. Okuhira, Y. Demizu, H. Inoue, M. Naito, M. Kurihara*
  • Journal Title: Bioorg. Med. Chem. Volume: 23 Issue: 13 Pages: 3091-3096
  • DOI: 10.1016/j.bmc.2015.05.002
  • Peer Reviewed
• [Journal Article] Development of cell-penetrating R7 fragment-conjugated helical peptides as inhibitors of estrogen receptor-mediated transcription. (2014)
  • Author(s): 2.Nagakubo, T., Demizu, Y., Kanda, Y., Misawa, T., Shoda, T., Okuhira, K., Sekino., Y., Naito, M. and Kurihara, M
  • Journal Title: Bioconjug Chem. Volume: 25 Issue: 11 Pages: 1921-24
  • DOI: 10.1021/bc500480e
  • Peer Reviewed
• [Journal Article] Cancer cell death induced by novel small molecules degrading the TACC3 protein via the ubiquitin proteasome pathway. (2014)
  • Author(s): 1.Ohoka, N., Nagai, K., Hattori, T., Okuhira, K., Shibata, N., Cho, N. and Naito, M
  • Journal Title: Cell Death Dis. Volume: 5 Issue: 11 Pages: e1513-e1513
  • DOI: 10.1038/cddis.2014.471
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Design and synthesis of tamoxifen derivatives as a selective estrogen receptor down-regulator. (2014)
  • Author(s): Shoda, T., Okuhira, K., Kato, M., Demizu, Y., Inoue, H., Naito, M., and Kurihara, M.
  • Journal Title: Bioorg Med Chem Lett Volume: 24 Issue: 1 Pages: 87-89
  • DOI: 10.1016/j.bmcl.2013.11.078
  • Peer Reviewed
• [Journal Article] Development of hybrid small molecules that induce degradation of estrogen receptor-alpha and necrotic cell death in breast cancer cells. (2013)
  • Author(s): Okuhira, K., Demizu, Y., Hattori, T., Ohoka, N., Shibata, N., Nishimaki-Mogami, T., Okuda, H., Kurihara, M., Natiro, M.
  • Journal Title: Cancer Science Volume: 104 Issue: 11 Pages: 1492-1498
  • DOI: 10.1111/cas.12272
  • Peer Reviewed
• [Presentation] 網羅的人工ユビキチン修飾システムの構築 (2016)
  • Author(s): 大岡 伸通, 伊東 昌宏, 奥平 桂一郎, 永井 克典, 柴田 識人, 服部 隆行, 長 展生, 内藤 幹彦
  • Organizer: 日本薬学会第136年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-03-26
• [Presentation] ユビキチン・プロテアソーム経路を利用したプロテインノックダウン化合物の開発 (2016)
  • Author(s): 服部 隆行, 正田 卓司, 奥平 桂一郎, 柴田 識人, 大岡 伸通, 伊藤 進, 栗原 正明, 内藤 幹彦
  • Organizer: 日本薬学会第136年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-03-26
• [Presentation] エストロゲン受容体転写活性化阻害ペプチドの創製 (2015)
  • Author(s): 出水 庸介, 長久保 貴哉, 三澤 隆史, 諫田 泰成, 奥平 桂一郎, 関野 祐子, 内藤 幹彦, 栗原 正明
  • Organizer: 日本薬学会第135年会
  • Place of Presentation: 神戸学院大学（兵庫県・神戸市）
  • Year and Date: 2015-03-25 – 2015-03-28
• [Presentation] ユビキチン・プロテアソームシステムを利用した TACC3 分解誘導剤の開発と抗がん活性評価 (2015)
  • Author(s): 大岡 伸通, 永井 克典, 服部 隆行, 奥平 桂一郎, 柴田 識人, 長 展生, 内藤 幹彦
  • Organizer: 日本薬学会第135年会
  • Place of Presentation: 神戸学院大学（兵庫県・神戸市）
  • Year and Date: 2015-03-25 – 2015-03-28
• [Presentation] タモキシフェン骨格を有する分解誘導剤のアルキル鎖長および末端構造の最適化 (2015)
  • Author(s): 正田 卓司, 加藤 雅士, 藤里 卓磨, 原田 麟太郎, 奥平 桂一郎, 井上 英史, 内藤 幹彦, 栗原 正明
  • Organizer: 日本薬学会第135年会
  • Place of Presentation: 神戸学院大学（兵庫県・神戸市）
  • Year and Date: 2015-03-25 – 2015-03-28
• [Presentation] Bestatin/tamoxifen hybrid molecule induces proteasomal degradation of estrogen receptor a and necrotic cell death in breast cancer cells (2014)
  • Author(s): Okuhira K, Demizu Y, Ohoka N, Shibata N, Hattori T, Nishimaki-Mogami T, Kurihara M, Okuda H, Naito M
  • Organizer: Keystone Symposia on Molecular and Cellular Biology, The Ubiquitin System: From Basic Science to Drug Discovery
  • Place of Presentation: 米国ビッグスカイ
• [Presentation] エストロゲン受容体分解誘導剤による乳癌の細胞死誘導分子機構 (2014)
  • Author(s): 奥平桂一郎，出水庸介，服部隆行，大岡伸通，柴田識人，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134年会
  • Place of Presentation: 熊本市
• [Presentation] タモキシフェン骨格を有する新規エストロゲン受容体分解誘導剤の開発 (2014)
  • Author(s): 加藤雅士，正田卓司，奥平桂一郎，井上英史，内藤幹彦， 栗原正明
  • Organizer: 日本薬学会第134年会
  • Place of Presentation: 熊本市
• [Presentation] エストロゲン受容体転写阻害ペプチドの創製 (2014)
  • Author(s): 長久保貴哉，出水庸介，佐藤由紀子，諫田泰成，奥平桂一郎，関野祐子，内藤幹彦，栗原正明
  • Organizer: 日本薬学会第134年会
  • Place of Presentation: 熊本市
• [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効果の検討 (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: 第17回日本がん分子標的治療学会学術集会
  • Place of Presentation: 京都市
• [Presentation] SNIPER induces ubiquitylation and proteasomal degradation of estrogen receptor 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: The 35th Naito Conference; The Ubiquitin-Proteasome System
  • Place of Presentation: 札幌市
• [Presentation] Development of hybrid small molecules that induce degradation of estrogen receptor-alpha and necrotic cell death in breast cancer cells (2013)
  • Author(s): Okuhira K, Demizu Y, Hattori T, Ohoka N, Shibata N, Nishimaki-Mogami, T, Okuda H, Kurihara M, Naito M
  • Organizer: AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics
  • Place of Presentation: 米国ボストン
• [Presentation] エンドキシフェン骨格を持つ新規エストロゲン受容体分解誘導剤の開発 (2013)
  • Author(s): 加藤雅士，正田卓司，奥平桂一郎，井上英史，内藤幹彦，栗原正明
  • Organizer: 第31回メディシナルケミストリーシンポジウム
  • Place of Presentation: 広島市