Design of peptide ligands based on protein-protein interaction and their application to protein knockdown technology

• Project/Area Number: 16K15121
• 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, 遺伝子医薬部, 部長 (00198011)
• Co-Investigator(Kenkyū-buntansha): 大岡 伸通 国立医薬品食品衛生研究所, 遺伝子医薬部, 室長 (80568519)
• Co-Investigator(Renkei-kenkyūsha): DEMIZU Yosuke 国立医薬品食品衛生研究所, 有機化学部, 部長 (90389180)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: プロテインノックダウン / SNIPER / ヘリカルペプチド / エストロゲン受容体 / Notch / 蛋白質分解 / ユビキチン / プロテアソーム / ペプチド / 核内受容体 / 蛋白質

Outline of Final Research Achievements

We developed novel SNIPER compounds against estrogen receptor and Notch1 proteins by incorporating helical peptides, PERM3 and SAHM1, respectively, to SNIPERs as target ligands. These SNIPER compounds induced proteasomal degradation of the target proteins, and a SNIPER(Notch) suppressed the expression of c-myc, a downstream gene regulated by Notch signaling. These results indicate that functional SNIPER compounds can be developed by incorporating helical peptides as a target ligand.

Research Products

• [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] 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] Development of Protein Degradation Inducers of Androgen Receptor by Conjugation of Androgen Receptor Ligands and Inhibitor of Apoptosis Protein Ligands (2017)
  • Author(s): Shibata Norihito、Nagai Katsunori、Morita Yoko、Ujikawa Osamu、Ohoka Nobumichi、Hattori Takayuki、Koyama Ryokichi、Sano Osamu、Imaeda Yasuhiro、Nara Hiroshi、Cho Nobuo、Naito Mikihiko
  • Journal Title: Journal of Medicinal Chemistry Volume: 61 Issue: 2 Pages: 543-575
  • DOI: 10.1021/acs.jmedchem.7b00168
  • Peer Reviewed
• [Journal Article] Simple and efficient knockdown of His-tagged proteins by ternary molecules consist of His-tag ligand, ubiquitin ligase ligand and cell penetrating peptide (2017)
  • Author(s): T. Hattori, K. Okitsu, N. Yamazaki, N. Ohoka, N. Shibata, T. Misawa, M. Kurihara, Y. Demizu,* M. Naito*
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 27 Issue: 18 Pages: 4478-4481
  • DOI: 10.1016/j.bmcl.2017.08.001
  • Peer Reviewed
• [Journal Article] SNIPER(TACC3) induces cytoplasmic vacuolization and sensitizes cancer cells to Bortezomib. (2017)
  • Author(s): Ohoka, N., Nagai, K., Shibata, N., Hattori, T., Nara, H., Cho, N. & Naito, M.
  • Journal Title: Cancer Sci Volume: 108 Issue: 5 Pages: 1032-1041
  • DOI: 10.1111/cas.13198
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Development of protein degradation inducers of oncogenic BCR-ABL protein by conjugation of ABL kinase inhibitors and IAP ligands (2017)
  • Author(s): Shibata Norihito、Miyamoto Naoki、Nagai Katsunori、Shimokawa Kenichiro、Sameshima Tomoya、Ohoka Nobumichi、Hattori Takayuki、Imaeda Yasuhiro、Nara Hiroshi、Cho Nobuo、Naito Mikihiko
  • Journal Title: Cancer Science Volume: 108 Issue: 8 Pages: 1657-1666
  • DOI: 10.1111/cas.13284
  • Peer Reviewed / Open Access
• [Journal Article] Targeting the Allosteric Site of Oncoprotein BCR-ABL as an Alternative Strategy for Effective Target Protein Degradation (2017)
  • Author(s): Shimokawa Kenichiro、Shibata Norihito、Sameshima Tomoya、Miyamoto Naoki、Ujikawa Osamu、Nara Hiroshi、Ohoka Nobumichi、Hattori Takayuki、Cho Nobuo、Naito Mikihiko
  • Journal Title: ACS Medicinal Chemistry Letters Volume: 8 Issue: 10 Pages: 1042-1047
  • DOI: 10.1021/acsmedchemlett.7b00247
  • Peer Reviewed
• [Journal Article] Development of helix-stabilized cell-penetrating peptides containing cationic α,α-disubstituted amino acids as helical promoters. (2017)
  • Author(s): Yamashita H, Misawa T, Oba M, Tanaka M, Naito M, Kurihara M, Demizu Y.
  • Journal Title: Bioorg Med Chem. Volume: 25(6) Issue: 6 Pages: 1846-1851
  • DOI: 10.1016/j.bmc.2017.01.044
  • 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] In Vivo Knockdown of Pathogenic Proteins via Specific and Nongenetic Inhibitor of Apoptosis Protein (IAP)-dependent Protein Erasers (SNIPERs). (2017)
  • Author(s): Ohoka, N., Okuhira, K., Ito, M., Nagai, K., Shibata, N., Hattori, T., Ujikawa, O., Shimokawa, K., Sano, O., Koyama, R., Fujita, H., Teratani, M., Matsumoto, H., Imaeda, Y., Nara, H., Cho, N. & Naito, M.
  • Journal Title: J Biol Chem Volume: 292 Issue: 11 Pages: 4556-4570
  • DOI: 10.1074/jbc.m116.768853
  • Peer Reviewed / Int'l Joint Research / 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
• [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 (2017)
  • Author(s): 大岡伸通、永井克典、奥平桂一郎、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: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2017-03-25
• [Presentation] プロテインノックダウン法を利用したアンドロゲン受容体蛋白質分解誘導剤の開発 (2017)
  • Author(s): 柴田識人、大岡伸通、服部隆行、永井克典、伊東昌宏、奈良洋、長展生、内藤幹彦
  • Organizer: 日本薬学会第136年会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2017-03-25
• [Presentation] ユビキチンープロテアソーム系を介したHisタグタンパク質分解誘導分子の開発 (2017)
  • Author(s): 沖津航陽，服部隆行，出水庸介，三澤隆史，正田卓司，内藤幹彦，栗原正明
  • Organizer: 日本薬学会第136年会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2017-03-25
• [Presentation] IAPアンタゴニストLCL161誘導体を導入したSNIPERによる効果的なプロテインノックダウン (2017)
  • Author(s): 大岡伸通、奥平桂一郎、伊東昌宏、永井克典、柴田識人、服部隆行、宇治川治、下川賢一郎、佐野修、小山亮吉、今枝泰宏、奈良洋、長展生、内藤幹彦
  • Organizer: 第21回日本がん分子標的治療学会学術集会
• [Presentation] Targeting the allosteric site of oncogenic BCR-ABL protein as an alternative strategy for effective protein degradation (2017)
  • Author(s): Norihito Shibata, Kenichiro Shimokawa, Tomoya Sameshima, Naoki Miyamoto, Osamu Ujikawa, Hiroshi Nara, Nobumichi Ohoka, Takayuki Hattori, Nobuo Cho, Mikihiko Naito
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] 芳香族炭化水素受容体ユビキチンリガーゼをリクルートする新しいプロテインノックダウン化合物の開発 (2017)
  • Author(s): 大岡伸通、柴田識人、服部隆行、内藤幹彦
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] 低コピーEGFR L858R変異アレルを有する細胞の作製とEGFR阻害剤感受性の解析 (2017)
  • Author(s): 築茂由則、鈴木孝昌、内藤幹彦
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Degradation of oncogenic proteins by SNIPER compounds. (2017)
  • Author(s): Mikihiko Naito, Nobumichi Ohoka, Norihito Shibata, Takayuki Hattori
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] NCCオンコパネルの90遺伝子を網羅する変異細胞株パネルの作製 (2017)
  • Author(s): 鈴木孝昌、築茂由則、内藤幹彦、小原有弘
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Development of protein degradation inducers of oncogenic BCR-ABL protein by conjugation of ABL kinase inhibitors and IAP ligands (2017)
  • Author(s): Norihito Shibata, Naoki Miyamoto, Katsunori Nagai, Kenichiro Shimokawa, Tomoya Sameshima, Nobumichi Ohoka, Takayuki Hattori, Yasuhiro Imaeda, Hiroshi Nara, Nobuo Cho, Mikihiko Naito
  • Organizer: 日本薬学会第138年会
• [Presentation] In vivo protein knockdown by chimeric small-compound SNIPERs. (2017)
  • Author(s): Nobumichi Ohoka, Yoko Morita, Katsunori Nagai, Kenichiro Shimokawa, Osamu Ujikawa, Ikuo Fujimori, Masahiro Ito, Youji Hayase, Keiichiro Okuhira, Norihito Shibata, Takayuki Hattori, Tomoya Samejima, Osamu Sano, Ryokichi Koyama, Yasuhiro Imaeda, Hiroshi Nara, Nobuo Cho, Mikihiko Naito
  • Organizer: 日本薬学会第138年会
• [Presentation] IAPを利用したプロテインノックダウン法の開発とがん原性タンパク質の分解 (2017)
  • Author(s): 内藤幹彦、大岡伸通、柴田識人、服部隆行
  • Organizer: 日本薬学会第138年会
  • Invited
• [Presentation] Protein knockdown by SNIPER compounds recruiting IAP ubiquitin ligases (2017)
  • Author(s): Mikihiko Naito
  • Organizer: 2017 Chinese Medicinal Chemistry Symposium, CPA-EFMC International Symposium on Medicinal Chemistry
  • Int'l Joint Research / Invited
• [Presentation] Degradation of target proteins by SNIPER compounds recruiting IAP ubiquitin ligases (2017)
  • Author(s): Mikihiko Naito, Nobumichi Ohoka, Norihito Shibata, Takayuki Hattori
  • Organizer: EMBO conference Ubiquitin and SUMO
  • Int'l Joint Research
• [Presentation] In vivo protein knockdown by SNIPER recruiting IAP ubiquitin ligases (2016)
  • Author(s): Mikihiko Naito
  • Organizer: The 21th 国際化学療法シンポジウム
  • Place of Presentation: 日本科学未来館（東京）
  • Year and Date: 2016-12-14
  • Int'l Joint Research / Invited
• [Presentation] Development of hybrid small molecules that induce degradation of oncogenic BCR-ABL (2016)
  • Author(s): Norihito Shibata, Nobumichi Ohoka, Takayuki Hattori, Mikihiko Naito
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 横浜国際会議場（神奈川県横浜市）
  • Year and Date: 2016-10-06
• [Presentation] 低分子化合物SNIPERによるin vivoプロテインノックダウンと抗腫瘍活性評価 (2016)
  • Author(s): 大岡伸通、奥平桂一郎、永井克典、伊東昌宏、柴田識人、服部隆行、宇治川治、佐野修、小山亮吉、今枝泰宏、奈良洋、長展生、内藤幹彦
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 横浜国際会議場（神奈川県横浜市）
  • Year and Date: 2016-10-06
• [Presentation] 低分子化合物SNIPERによるin vivoプロテインノックダウン (2016)
  • Author(s): 大岡伸通、奥平桂一郎、柴田識人、服部隆行、内藤幹彦
  • Organizer: 第20回日本がん分子標的治療学会学術集会
  • Place of Presentation: 別府コンベンションセンター（大分県別府市）
  • Year and Date: 2016-05-30
• [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: 別府コンベンションセンター（大分県別府市）
  • Year and Date: 2016-05-30
• [Remarks] 国立医薬品食品衛生研究所遺伝子医薬部 研究概要
  • URL: http://www.nihs.go.jp/mtgt/research.html