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

2016 Fiscal Year Final Research Report

• 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
• 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

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.

Free Research Field

生化学、分子生物学、ケミカルバイオロジー