Elucidation of the mechanism of action of cereblon modulators on acute promyelocytic leukemia (APL)

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K16378
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47040:Pharmacology-related
• Research Institution: Oita University (2020); Tokyo Medical University (2019)
• Principal Investigator: Shimizu Nobuyuki 大分大学, 医学部, 助教 (30817143)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: セレブロン（CRBN） / E3ユビキチンリガーゼ / サリドマイド / レナリドミド / ポマリドミド / ネオ基質 / 融合遺伝子 / 急性前骨髄球性白血病（APL）

Outline of Final Research Achievements

In this study, we aimed to expand the indication of pomalidomide, which is approved for the treatment of multiple myeloma. Cereblon (CRBN) is a unique protein that binds to and recognizes and degrades unusual substrates (neo-substrates), collectively known as cereblon modulators. I had discovered a new neo-substrate for one of the cereblon modulators, pomalidomide. The gene encoding the neo-substrate has been implicated in acute promyelocytic leukemia (APL), a blood cancer. The analysis showed that pomalidomide induced the degradation of the new neo-substrate in a celebron-dependent manner and had an anticancer effect on APL. These results suggest a new therapeutic approach for APL based on the novel neo-substrate of pomalidomide.

Free Research Field

ケミカルバイオロジー

Academic Significance and Societal Importance of the Research Achievements

ポマリドミドは、再発性の多発性骨髄腫に対して既に承認された薬である。本研究成果により、ポマリドミドが急性前骨髄球性白血病（APL）の治療薬へと適応追加されることが期待できる。また、その臨床試験に対するコストと時間が大幅に削減できる点からも、社会的な波及効果は高いと考えられる。