Elucidation of the molecular mechanism of the anti-cancer activity of IMiDs
| Project/Area Number |
26750374
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Chemical biology
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| Research Institution | Tokyo Medical University |
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Principal Investigator |
Ito Takumi 東京医科大学, 医学部, 准教授 (30533179)
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| Project Period (FY) |
2014-04-01 – 2017-03-31
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| Project Status |
Completed (Fiscal Year 2016)
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| Budget Amount *help |
¥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)
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| 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.
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Report
(4 results)
Research Products
(19 results)
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[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.
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Journal Title
Nature
Volume: 535
Issue: 7611
Pages: 252-257
DOI
Related Report
Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
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[Journal Article] Structure of the human cereblon-DDB1- lenalidomide complex reveals basis for responsiveness to thalidomide analogs2014
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
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Journal Title
Nat. Struct. Mol. Biol.
Volume: 21
Issue: 9
Pages: 803-809
DOI
Related Report
Peer Reviewed
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