Elucidation of the molecular mechanism of the anti-cancer activity of IMiDs

• Project/Area Number: 26750374
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Chemical biology
• 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): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: セレブロン / ユビキチン / GSPT1 / IMiDs / CC-885 / レナリドミド / ポマリドミド / サリドマイド / 急性骨髄性白血病 / ユビキチンリガーゼ

Outline of Final Research Achievements

In this project, I investigated new substrates of the CRBN E3 ubiquitin ligase in the presence of Immunomodulatory drugs (IMiDs). A new compound, CC-885 was isolated by phenotypic screenings using various cell lines in Celgene. Among them acute myeloid leukemia (AML) cells were very sensitive to CC-885. I isolated a translation termination factor GSPT1, as a new substrate of the CRBN ubiquitin ligase. This study revealed that CC-885 induced anti-proliferative effect on AML cells through GSPT1 degradation. Furthermore, collaborative studies with Celgene revealed CRBN-CC-885-GSPT1 X-ray structure. CC-885 was shown to provide the interaction hotspot in CRBN for binding to GSPT1. Furthermore, we found a specific glycine of the substrate is critical for binding to CRBN in the presence of a ligand such as CC-885. This study resents a new therapeutic target for the treatment of AML and the structural basis of the CRBN-ligand-substrate complex.

Research Products

• [Int'l Joint Research] Celgene Corporation(米国)
• [Int'l Joint Research] Celgene Corporation(米国)
• [Journal Article] A novel cereblon modulator recruits GSPT1 to the CRL4(CRBN) ubiquitin ligase. (2016)
  • Author(s): Matyskiela ME, 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 GC, Gaidarova S, Xu S, Ruchelman AL, Handa H, Carmichael J, Daniel TO, Cathers BE, Lopez-Girona A, Chamberlain PP.
  • Journal Title: Nature Volume: 535 Issue: 7611 Pages: 252-257
  • DOI: 10.1038/nature18611
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Cereblon and its downstream substrates as molecular targets of immunomodulatory drugs. (2016)
  • Author(s): Ito T and Handa H.
  • Journal Title: Int J Hematol Volume: 104 Issue: 3 Pages: 293-299
  • DOI: 10.1007/s12185-016-2073-4
  • Peer Reviewed
• [Journal Article] Discovery of the target for immunomodulatory drugs (IMiDs) (2016)
  • Author(s): 伊藤拓水、安藤秀樹、半田宏
  • Journal Title: Rinsho Ketsueki Volume: 57 Issue: 5 Pages: 556-562
  • DOI: 10.11406/rinketsu.57.556
  • NAID: 130005155372
  • ISSN: 0485-1439, 1882-0824
• [Journal Article] サリドマイドの標的ユビキチンリガーゼ“セレブロン”とその機能 (2016)
  • Author(s): 伊藤拓水、半田宏
  • Journal Title: 医学のあゆみ Volume: 256 Pages: 891-895
• [Journal Article] Myeloid disease: Another action of a thalidomide derivative (2015)
  • Author(s): Takumi Ito, Hiroshi Handa
  • Journal Title: Nature Volume: 523 Issue: 7559 Pages: 167-168
  • DOI: 10.1038/nature14628
  • Peer Reviewed / Open Access
• [Journal Article] 半田ビーズを用いたサリドマイド標的同定 (2015)
  • Author(s): 坂本聡、伊藤拓水、半田宏
  • Journal Title: CSJカレントレビュー Volume: 19 Pages: 86-93
• [Journal Article] Structure of the human cereblon-DDB1- lenalidomide complex reveals basis for responsiveness to thalidomide analogs (2014)
  • Author(s): P. Chamberlain, A. Lopez-Girona, K. Miller, G. Carmel, B. Pagarigan, B. Chie-Leon, E. Rychak, L. Corral, Y. Ren, M. Wang, M. Riley, S. Delker, T. Ito, H. Ando, T. Mori, Y. Hirano, H. Handa, T. Hakoshima, T. Daniel, B. Cathers
  • Journal Title: Nat. Struct. Mol. Biol. Volume: 21 Issue: 9 Pages: 803-809
  • DOI: 10.1038/nsmb.2874
  • Peer Reviewed
• [Presentation] 急性骨髄性白血病に効果を示す新規のセレブロンモジュレーター (2016)
  • Author(s): 伊藤拓水、半田宏
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜、横浜
  • Year and Date: 2016-11-30
• [Presentation] 急性骨髄性白血病に有効な新規セレブロンモジュレーターの開発 (2016)
  • Author(s): 伊藤拓水、半田宏
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台国際センター、仙台
  • Year and Date: 2016-09-25
• [Presentation] リガンド依存的ユビキチンリガーゼCRBNの制御機構 (2016)
  • Author(s): 伊藤拓水、朝妻知子、山本淳一、安藤秀樹、佐藤智美、山口雄輝、半田宏
  • Organizer: 日本ケミカルバイオロジー学会第11回年会
  • Place of Presentation: 京都テルサ, 京都
  • Year and Date: 2016-06-15
• [Presentation] Cereblon is a substrate receptor of the Cul4 ubiquitin ligase whose substrate recognition is modulated by IMiDs. (2014)
  • Author(s): 伊藤拓水、安藤秀樹、山口雄輝、半田宏
  • Organizer: 日本分子生物学会
  • Place of Presentation: パシフィコ横浜、神奈川
  • Year and Date: 2014-11-26
• [Presentation] Cereblon is a substrate receptor of the Cul4 ubiquitin ligase whose substrate recognition is modulated by IMiDs. (2014)
  • Author(s): 伊藤拓水、安藤秀樹、山口雄輝、半田宏
  • Organizer: Cold Spring Harbor Asia - Protein Modification & Homeostasis conference
  • Place of Presentation: 蘇州、中国
  • Year and Date: 2014-06-18
  • Invited
• [Book] IMiDs（免疫調整薬）の現状と展望 (2015)
  • Author(s): 伊藤拓水、安藤秀樹、半田宏
  • Total Pages: 233
  • Publisher: （株）メディカルレビュー社
• [Book] 生物活性分子の標的同定と機能解明（CSJカレントビュー第19号） (2015)
  • Author(s): 坂本聡、伊藤拓水、半田宏
  • Total Pages: 189
  • Publisher: （株）化学同人
• [Book] 日本臨牀（特集：多発性骨髄腫の病態と最新治療―基礎と臨床の最新情報ー (2015)
  • Author(s): 伊藤拓水、安藤秀樹、半田宏
  • Total Pages: 182
  • Publisher: （株）日本臨牀社
• [Book] Organ Biology 21巻２号 (2014)
  • Author(s): 伊藤拓水、安藤秀樹、半田宏
  • Total Pages: 273
  • Publisher: （株）日本医学館
• [Patent(Industrial Property Rights)] METHODS OF USING AN ACTIVATOR OF CEREBLON FOR NEURAL CELL EXPANSION AND THE TREATMENT OF CENTRAL NERVOUS SYSTEM DISORDERS (2015)
  • Inventor(s): Handa H, Ando H, Ito H
  • Industrial Property Rights Holder: Handa H, Ando H, Ito H
  • Industrial Property Rights Type: 特許
  • Filing Date: 2015-02-23
  • Acquisition Date: 2015-08-27
  • Overseas