Elucidation of the molecular basis of IMiDs' action

• Project/Area Number: 17H04213
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Tokyo Medical University
• Principal Investigator: Ito Takumi 東京医科大学, 医学部, 准教授 (30533179)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000); Fiscal Year 2019: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2018: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2017: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
• Keywords: サリドマイド / セレブロン / ユビキチン / PROTACs / CRBN / IMiDs / ネオ基質 / タンパク質分解 / ケミカルバイオロジー / 骨髄腫

Outline of Final Research Achievements

In this study, I aimed to elucidate the mechanistic basis of the CRBN-based IMiDs signaling. I have analyzed a substrate candidate S1 and a non-substrate X1 of CRBN, a substrate receptor of CRL4 E3 ubiquitin ligase. I found S1 is an exact IMiD-dependent CRBN substrate and is responsible for anti-DLBCL (Diffused Large B-Cell Lymphoma) and anti-angiogenesis other than anti-myeloma effects of IMiDs. I also found the structural degron of S1. I determined the CRBN-binding domain in X1. I newly isolated and analyzed several new CRBN neosubstrates.

Academic Significance and Societal Importance of the Research Achievements

免疫調節薬(IMiDs)は現在、多発性骨髄腫などの優れた治療薬として世界的にも脚光を浴びているが、その分子基盤について不明な点が多かった。今回、研究代表者によりIMiDsの標的であるCRBNのさらに下流に位置するS1および他の基質の実態が明らかになった。S1はびまん性大細胞型B細胞リンパ腫や血管新生などにも関わることが判明し、IMiDsのさらなる適応拡大に貢献できる成果をあげられたといえる。

Research Products

• [Int'l Joint Research] ミラノ大学(イタリア)
• [Int'l Joint Research] セルジーン社/カリフォルニア大学ロサンゼルス校(米国)
• [Int'l Joint Research] 米国セルジーン社(米国)
• [Int'l Joint Research] Celgene Corporation(米国)
• [Journal Article] Genome-wide screening reveals a role for subcellular localization of CRBN in the anti-myeloma activity of pomalidomide (2020)
  • Author(s): Tateno Shumpei、Iida Midori、Fujii Satoshi、Suwa Tetsufumi、Katayama Miki、Tokuyama Haruka、Yamamoto Junichi、Ito Takumi、Sakamoto Satoshi、Handa Hiroshi、Yamaguchi Yuki
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 4012-4012
  • DOI: 10.1038/s41598-020-61027-w
  • Peer Reviewed / Open Access
• [Journal Article] p63 is a cereblon substrate involved in thalidomide teratogenicity (2019)
  • Author(s): Asatsuma-Okumura Tomoko、Ando Hideki、De Simone Marco、Yamamoto Junichi、Sato Tomomi、Shimizu Nobuyuki、Asakawa Kazuhide、Yamaguchi Yuki、Ito Takumi、Guerrini Luisa、Handa Hiroshi
  • Journal Title: Nature Chemical Biology Volume: 15 Issue: 11 Pages: 1077-1084
  • DOI: 10.1038/s41589-019-0366-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cereblon Control of Zebrafish Brain Size by Regulation of Neural Stem Cell Proliferation (2019)
  • Author(s): Hideki Ando, Tomomi Sato, Takumi Ito, Junichi Yamamoto, Satoshi Sakamoto, Nobuhiro Nitta, Tomoko Asatsuma-Okumura, Nobuyuki Shimizu, Ryota Mizushima, Ichio Aoki, Takeshi Imai, Yuki Yamaguchi, Arnold J Berk, and Hiroshi Handa
  • Journal Title: iScience Volume: 15 Pages: 95-108
  • DOI: 10.1016/j.isci.2019.04.007
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Molecular mechanisms of cereblon-based drugs (2019)
  • Author(s): Asatsuma-Okumura Tomoko、Ito Takumi、Handa Hiroshi
  • Journal Title: Pharmacology & Therapeutics Volume: 202 Pages: 132-139
  • DOI: 10.1016/j.pharmthera.2019.06.004
  • Peer Reviewed
• [Journal Article] NQO1 inhibits the TLR-dependent production of selective cytokines by promoting IκB-ζ degradation. (2018)
  • Author(s): 1. Kimura, A., Kitajima, M., Nishida, K., Serada, S., Fujimoto, M., Naka, T., Fuji-Kuriyama, Y., Ito, T., Handa, H., Tanaka, T, Yoshimura, A., Suzuki, H.
  • Journal Title: Journal of experimental medicine Volume: 215 Issue: 8 Pages: 2197-2200
  • DOI: 10.1084/jem.20172024
  • Peer Reviewed / Open Access
• [Journal Article] Structural basis of thalidomide enantiomer binding to cereblon. (2018)
  • Author(s): Mori, T., Itoh, T., Liu, S., Ando, H., Sakamoto, S., Yamaguchi, Y., Tokunaga, E., Shibata, N., Handa, H. and Hakoshima, T.
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 1294-1294
  • DOI: 10.1038/s41598-018-19202-7
  • Peer Reviewed / Open Access
• [Presentation] セレブロンを標的とする薬剤の分子機構 (2019)
  • Author(s): 伊藤拓水
  • Organizer: バイオインタラクション研究会 第６回ワークショップ
  • Invited
• [Presentation] 新規セレブロンモジュレーターの分子機構の解析 (2018)
  • Author(s): 伊藤拓水、半田宏
  • Organizer: 第41回分子生物学会年会
• [Presentation] セレブロンモジュレーターによるユビキチンリガーゼ制御工学 (2018)
  • Author(s): 伊藤拓水、 半田宏
  • Organizer: 日本薬学会第138年会
  • Invited
• [Presentation] Ligand-directed degradation of GSPT1 by a novel cereblon modulator drives potent antitumor effects (2017)
  • Author(s): Matyskiela M, Lu G, Ito T, Pagarigan B, Lu CC, Miller K, Fang W, Wang NY, Nguyen D, Houston J, Carmel G, Tran T, Riley M, Nosaka L, Lander G, Gaidarova S, Xu S, Ruchelman A, Handa H, Carmichale J, Daniel TO, Cathers BE, Lopez-Girona A and Chamberlain P
  • Organizer: AACR Annual Meeting 2017
• [Remarks] サリドマイドが手足や耳に奇形を引き起こすメカニズムを解明 ― 安全なサリドマイド系新薬の開発へ ―
  • URL: https://www.tokyo-med.ac.jp/news/media/docs/20191008pressrelease.pdf
• [Remarks] サリドマイドの標的タンパク質セレブロンが脳の神経幹細胞の増殖 を制御することを解明
  • URL: https://www.tokyo-med.ac.jp/news/media/docs/20190513pressrelease.pdf