Development of novel small molecules degrading microtubule-associated proteins

• Project/Area Number: 26860049
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Biological pharmacy
• Research Institution: National Institute of Health Sciences
• Principal Investigator: Ohoka Nobumichi 国立医薬品食品衛生研究所, 遺伝子医薬部, 室長 (80568519)
• Research Collaborator: Naito Mikihiko 国立医薬品食品衛生研究所, 遺伝子医薬部, 部長 (00198011)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: TACC3 / SNIPER / ユビキチン / プロテアソーム / がん / 細胞死 / IAP

Outline of Final Research Achievements

We have developed SNIPER compounds that induce selective degradation of target proteins. In this study, we designed and synthesized SNIPER(TACC3)s, which target the spindle regulatory protein TACC3. SNIPER(TACC3)s induce ubiquitylation and proteasomal degradation of TACC3 in cells. Mechanistic analysis indicated that APC/CCDH1 mediates the SNIPER(TACC3)-induced degradation of TACC3. SNIPER(TACC3) selectively induced apoptosis in cancer cells expressing a larger amount of TACC3 than normal cells.
SNIPER(TACC3) also induced paraptosis-like cell death selectively in cancer cells. Mechanistic analysis suggests that accumulation of ubiquitylated protein aggregates that requires XIAP induces ER-stress responses involving XBP-1 and ER-derived vacuolization in cancer cells. Importantly, inhibition of proteasome enhanced SNIPER(TACC3)-induced vacuolization, and combination treatment of SNIPER(TACC3) and bortezomib exhibited a synergistic anticancer activity in several cancer cell lines.

Research Products

• [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] 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] Protein Knockdown Technology: Application of Ubiquitin Ligase to Cancer Therapy. (2016)
  • Author(s): Ohoka N, Shibata N, Hattori T, Naito M.
  • Journal Title: Current Cancer Drug Targets Volume: 16 Issue: 2 Pages: 136-146
  • DOI: 10.2174/1568009616666151112122502
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [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] Effects of alkyl side chains and terminal hydrophilicity on vitamin D receptor (VDR) agonistic activity based on the diphenylpentane skeleton (2015)
  • Author(s): Takashi Misawa, Momoko Yorioka, Yosuke Demizu, Tomomi Noguchi-Yachide, Nobumichi Ohoka, Megumi Kurashima-Kinoshita, Hitomi Motoyoshi, Hisao Nojiri, Atsushi Kittaka, Makoto Makishima, Mikihiko Naito, Masaaki Kurihara
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 25 Issue: 22 Pages: 5362-5366
  • DOI: 10.1016/j.bmcl.2015.09.030
  • Peer Reviewed / Int'l Joint Research
• [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
• [Presentation] 大岡伸通, 鈴木孝昌, 橋井則貴, 出水庸介, 栗原正明, 石井明子, 内藤幹彦 (2017)
  • Author(s): 分子標的薬オフターゲット効果の新しい評価法開発
  • Organizer: 日本薬学会第137年会
  • Place of Presentation: 仙台
  • Year and Date: 2017-03-24
• [Presentation] 低分子化合物SNIPERによる細胞内ユビキチン化機構の制御と創薬への応用 (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39回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-11-30
• [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, 柴田識人, 服部隆行, 内藤幹彦
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 横浜
  • 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, 服部隆行, 内藤幹彦
  • Organizer: 第20回日本がん分子標的治療学会
  • Place of Presentation: 大分
  • Year and Date: 2016-05-30
• [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): 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: 横浜
  • Year and Date: 2016-03-26
• [Presentation] ユビキチン化誘導剤によるユビキチン関連死の解明 (2015)
  • Author(s): 大岡伸通, 永井克典, 柴田識人, 服部隆行, 長展生, 内藤幹彦
  • Organizer: BMB2015（第38回日本分子生物学会年会、第88回日本生化学会大会 合同大会）
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-01
• [Presentation] Ubiquitin-related cancer cell death induced by small molecules degrading TACC3 protein. (2015)
  • Author(s): 大岡伸通, 柴田識人, 服部隆行, 内藤幹彦
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Presentation] TACC3分解誘導剤によるがん細胞のユビキチン関連死 (2015)
  • Author(s): 大岡伸通, 服部隆行, 内藤幹彦
  • Organizer: 第19回日本がん分子標的治療学会学術集会
  • Place of Presentation: 松山
  • Year and Date: 2015-06-10
• [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
  • 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分解誘導剤による癌細胞死の誘導. (2014)
  • 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: 第37回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] SNIPER(TACC3) degrades TACC3 protein via the ubiquitin-proteasome pathway and induces apoptosis in cancer cells expressing a large amount of TACC3. (2014)
  • 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: 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2014-11-18 – 2014-11-21
• [Presentation] ユビキチン・プロテアソームシステムを利用したTACC3分解誘導剤によるがん細胞死の誘導. (2014)
  • 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73回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Patent(Industrial Property Rights)] 複素環化合物 (2016)
  • Inventor(s): 内藤幹彦, 大岡伸通, 柴田識人, 奥平桂一郎, 他12名
  • Industrial Property Rights Holder: 内藤幹彦, 大岡伸通, 柴田識人, 奥平桂一郎, 他12名
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2016-196803
  • Filing Date: 2016-10-04