Novel small-molecule sirtuin inhibitors induce cell death in leukemia cells

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08851
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Fukuoka University
• Principal Investigator: Kozako Tomohiro 福岡大学, 薬学部, 准教授 (40398300)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: ATL / エピジェネティクス

Outline of Final Research Achievements

Adult T-cell leukemia (ATL) patients are refractory to treatment, and most acute-type patients die within 1 year of onset and have a poor prognosis. Therefore, the establishment of an ATL treatment method using a drug with a novel mechanism of action that effectively suppresses the growth of tumor cells is urgently needed. The novel SIRT2 inhibitor we synthesized led to cell death of ATL cells. It was also suggested that SRT1720 induces SIRT1-independent, caspase-independent apoptosis and cell death with autophagy, and has a tumor-suppressing effect. In the future, we would like to continue research and development so that drugs targeting sirtuins can become one of the options for leukemia treatment drugs.

Free Research Field

腫瘍薬理学

Academic Significance and Societal Importance of the Research Achievements

新規SIRT2阻害剤およびSRT1720がオートファジー細胞死を誘導することから、両薬剤の新たな細胞死の作用機序が明らかとなった。また、ATLモデルマウスにおいて、SRT1720は腫瘍量を有意に減少させた。興味深いことにSRT1720はSIRT1ノックダウン細胞においても細胞死を誘導したことから、SRT1720はSIRT1非依存的な経路で抗腫瘍効果を示すことが示唆された。
我々が合成した新規SIRT2阻害剤およびSRT1720をはじめとするサーチュインを標的とした薬剤が、白血病治療薬の選択肢の一つとなることができるよう、研究開発を継続していきたい。