Development of small molecule that recruit AhR E3 ligase to target proteins.

• Project/Area Number: 16K08340
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: International University of Health and Welfare (2017-2019); National Institute of Health Sciences (2016)
• Principal Investigator: Kurihara Masaaki 国際医療福祉大学, 薬学部, 教授 (20205206)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: プロテインノックダウン / 芳香族炭化水素受容体 / プロテインノックダウン法

Outline of Final Research Achievements

Targeted protein degradation using chimeric small molecules such as proteolysis-targeting chimeras (PROTACs) and specific and nongenetic inhibitors of apoptosis protein [IAP]-dependent protein erasers (SNIPERs) is an emerging modality in drug discovery. We expand the repertoire of E3 ligases capable of ubiquitylating target proteins using this system. By incorporating β-naphthoflavone (β-NF) as a ligand, we developed a novel class of chimeric molecules that recruit the arylhydrocarbon receptor (AhR) E3 ligase complex.

Academic Significance and Societal Importance of the Research Achievements

細胞内の目的とするタンパク質をユビキチン－プロテアソーム系によって意図的に分解する方法がプロテインノックダウン法である。疾病の原因タンパク質を特異的に分解できれば新しい治療薬の開発が可能となる。今後、プロテインノックダウン法は新しい創薬の手法となるであろう。この研究では、ユビキチンリガーゼ活性を有する芳香族炭化水素受容体を利用したプロテインノックダウン法の開発を行った。ここで開発したプロテインノックダウン法分子は乳がんの新しい治療薬の開発につながると考えられる。

Research Products

• [Journal Article] Development of small molecule chimeric degraders that bring target proteins and the aryl hydrocarbon receptor (AhR) E3 ligase into close proximity (2019)
  • Author(s): N. Ohoka, G. Tsuji, T. Shoda, T. Fujisato, M. Kurihara, Y. Demizu, M. Naito*
  • Journal Title: ACS Chem. Biol. Volume: 14 Issue: 12 Pages: 2822-2832
  • DOI: 10.1021/acschembio.9b00704
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Structural development of non-secosteroidal vitamin D receptor (VDR) ligands without any asymmetric carbon. (2018)
  • Author(s): Misawa T, Tsuji G, Takahashi T, Ochiai E, Takagi KI, Horie K, Kakuda S, Takimoto-Kamimura M, Kurihara M, Demizu Y.
  • Journal Title: Bioorg Med Chem. Volume: 26 Issue: 23-24 Pages: 6146-6152
  • DOI: 10.1016/j.bmc.2018.11.008
  • Peer Reviewed
• [Journal Article] Design and synthesis of cell-permeable fluorescent nitrilotriacetic acid derivatives. (2018)
  • Author(s): Tsuji G, Hattori T, Kato M, Hakamata W, Inoue H, Naito M, Kurihara M, Demizu Y, Shoda T.
  • Journal Title: Bioorg Med Chem. Volume: 26 Issue: 20 Pages: 5494-5498
  • DOI: 10.1016/j.bmc.2018.09.028
  • Peer Reviewed
• [Journal Article] Design and synthesis of estrogen receptor ligands with a 4-heterocycle-4-phenylheptane skeleton (2018)
  • Author(s): Eto Ryo、Misawa Takashi、Noguchi-Yachide Tomomi、Ohoka Nobumichi、Kurihara Masaaki、Naito Mikihiko、Tanaka Masakazu、Demizu Yosuke
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 26 Issue: 8 Pages: 1638-1642
  • DOI: 10.1016/j.bmc.2018.02.010
  • Peer Reviewed
• [Journal Article] Development of a small hybrid molecule that mediates degradation of His-tag fused proteins (2018)
  • Author(s): K. Okitsu, T. Hattori, T. Misawa, T. Shoda, M. Kurihara, M. Naito, Y. Demizu
  • Journal Title: J Med Chem. Volume: 61 Issue: 2 Pages: 576-582
  • DOI: 10.1021/acs.jmedchem.7b00413
  • Peer Reviewed
• [Journal Article] Targeted Degradation of Proteins Localized in Subcellular Compartments by Hybrid Small Molecules. (2017)
  • Author(s): Okuhira, K., Shoda, T., Omura, R., Ohoka, N., Hattori, T., Shibata, N., Demizu, Y., Sugihara, R., Ichino, A., Kawahara, H., Itoh, Y., Ishikawa, M., Hashimoto, Y., Kurihara, M., Itoh, S., Saito, H. & Naito, M.
  • Journal Title: Mol pharmacol Volume: 91 Issue: 3 Pages: 159-166
  • DOI: 10.1124/mol.116.105569
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Development of an ON/OFF switchable fluorescent probe targeting His tag fused proteins in living cells (2017)
  • Author(s): Okitsu K, Misawa T, Shoda T, Kurihara M, Demizu Y.
  • Journal Title: Bioorg Med Chem Lett. Volume: 27 Issue: 15 Pages: 3417-3422
  • DOI: 10.1016/j.bmcl.2017.05.087
  • Peer Reviewed
• [Journal Article] Development of a peptide-based inducer of protein degradation targeting NOTCH1 (2017)
  • Author(s): Ohoka N, Misawa T, Kurihara M, Demizu Y, Naito M.
  • Journal Title: Bioorg Med Chem Lett. Volume: 27 Issue: 22 Pages: 4985-4988
  • DOI: 10.1016/j.bmcl.2017.10.011
  • Peer Reviewed
• [Journal Article] Tamoxifen and fulvestrant hybrid showed potency as a selective estrogen receptor down-regulator (2017)
  • Author(s): Takuji Shoda, Masashi Kato, Takuma Fujisato, Yosuke Demizu, Hideshi Inoue, Mikihiko Naito, Masaaki Kurihara
  • Journal Title: Med. Chem. Volume: 13 Issue: 3 Pages: 206-213
  • DOI: 10.2174/1573406412666160805101408
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Development of a peptide-based inducer of nuclear receptors degradation. (2016)
  • Author(s): Demizu Y, Ohoka N, Nagakubo T, Yamashita H, Misawa T, Okuhira K, Naito M, Kurihara M.
  • Journal Title: Bioorg Med Chem Lett. Volume: 26 Issue: 11 Pages: 2655-2658
  • DOI: 10.1016/j.bmcl.2016.04.013
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Development of BCR-ABL degradation inducers via the conjugation of an imatinib derivative and a cIAP1 ligand. (2016)
  • Author(s): Demizu, Y., Shibata, N., Hattori, T., Ohoka, N., Motoi, H., Misawa, T., Shoda, T., Naito, M. & Kurihara, M.
  • Journal Title: Bioorg Med Chem Lett Volume: 26 Issue: 20 Pages: 4865-4869
  • DOI: 10.1016/j.bmcl.2016.09.041
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Plasmid DNA delivery by arginine-rich cell-penetrating peptides containing unnatural amino acids (2016)
  • Author(s): T. Kato, H. Yamashita, T. Misawa, K. Nishida, M. Kurihara, M. Tanaka, Y. Demizu, M. Oba
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 24 Issue: 12 Pages: 2681-2687
  • DOI: 10.1016/j.bmc.2016.04.031
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] 芳香族炭化水素受容体を利用したプロテインノックダウン法のメカニズム解析 (2017)
  • Author(s): 藤里卓磨, 正田卓司, 大岡伸通, 井上英史, 内藤幹彦, 栗原正明
  • Organizer: 日本薬学会第137年会
  • Place of Presentation: 仙台
  • Year and Date: 2017-03-25
• [Presentation] 選択的エストロゲン受容体分解薬の分子設計 (2017)
  • Author(s): 正田卓司, 藤里卓磨, 三澤隆史, 出水庸介, 井上英史, 内藤幹彦, 栗原正明
  • Organizer: 日本薬学会第137年会
  • Place of Presentation: 仙台
  • Year and Date: 2017-03-25
• [Presentation] 親水性分子の細胞内導入を志向した細胞膜高透過性ペプチドの開発 (2017)
  • Author(s): 三澤隆史，大岡伸通，大庭 誠，田中正一，内藤幹彦，栗原正明，出水庸介
  • Organizer: 第15回次世代を担う有機化学シンポジウム
• [Presentation] ジフェニルメタンを基本骨格とするリガンドの創製 (2017)
  • Author(s): 栗原正明，三澤隆史，出水庸介
  • Organizer: 第3回Neo Vitamin D Workshop学術集会
• [Presentation] 長鎖アルキル基を有する新規エストロゲン受容体分解誘導剤の合成と評価 (2016)
  • Author(s): 正田卓司，藤里卓磨，三澤隆史，出水庸介，井上英史，内藤幹彦，栗原正明
  • Organizer: 第42回反応と合成の進歩シンポジウム
  • Place of Presentation: 静岡
  • Year and Date: 2016-11-07
• [Presentation] エストロゲン受容体分解誘導剤の分子デザイン (2016)
  • Author(s): 正田卓司，奥平桂一郎，内藤幹彦，栗原正明
  • Organizer: 第20回日本がん分子標的治療学会学術集会
  • Place of Presentation: 別府
  • Year and Date: 2016-05-30