Searching for effective anti-cancer seed compounds for refractory cancers targeting AspH

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K15303
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47050:Environmental and natural pharmaceutical resources-related
• Research Institution: University of Toyama
• Principal Investigator: Nakashima Yu 富山大学, 学術研究部薬学・和漢系, 助教 (60902038)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Keywords: AspH / 2OG依存性酸化酵素 / 生薬 / 阻害剤

Outline of Final Research Achievements

AspH inhibitory activity tests were conducted on a library of 160 crude drug extracts and Chinese herbal medicine extracts held by the Institute of Natural Medicine at the University of Toyama. In the screening test for inhibitory activity, several crude drug and herbal medicine extracts were identified to exhibit AspH inhibitory activity in a concentration-dependent manner. In this study, natural compounds showing AspH inhibitory activity were isolated. Subsequently, co-crystallisation with AspH was conducted for natural products showing robust AspH inhibitory activity. The results of the X-ray crystallographic analysis successfully elucidated the mechanism of the AspH inhibitory machinery of the natural inhibitors.

Free Research Field

天然物化学

Academic Significance and Societal Importance of the Research Achievements

当該研究では複数の生薬や漢方方剤がAspH阻害活性を示すことを初めて明らかとした。さらに、その阻害活性を示す天然物の単離に成功することで、天然阻害剤のAspH阻害活性メカニズムの解明を化合物ベースで行う基盤構築を行なった。それに加え、AspH-天然阻害剤の複合体構造をX線結晶構造解析の手法により取得することに成功し、天然阻害剤のAspH阻害活性機構を明らかとした。AspH-天然阻害剤の複合体構造の取得には前例がなく、今後は得られた複合体X線結晶構造の阻害剤結合様式に基づき、天然阻害剤の官能基変換等を有機合成的に行うことで、AspHへの阻害活性や選択性を向上した阻害剤の開発につながる。