| Project/Area Number |
18H02559
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
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| Research Institution | University of Shizuoka |
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Principal Investigator |
Asai Akira 静岡県立大学, 薬学研究院, 教授 (60381737)
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| Co-Investigator(Kenkyū-buntansha) |
小郷 尚久 静岡県立大学, 薬学研究院, 講師 (20501307)
村岡 大輔 長崎大学, 医歯薬学総合研究科(医学系), 准教授 (20608955)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2020: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2019: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2018: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
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| Keywords | 抗がん剤 / トリプトファン / キヌレニン / IDO / TDO / 腫瘍微小環境 / がん免疫療法 / がん免疫 |
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| Outline of Final Research Achievements |
Recently the remarkable clinical benefits of immune checkpoint inhibitors (ICI) have been demonstrated in subgroups of cancer patients. However, there are still many non-responders who are resistant to ICI therapy. The kynurenine pathway driven by tryptophan metabolizing enzymes such as IDO and TDO are thought to be important for one of the resistance mechanisms of ICIs. We have identified various small molecule inhibitors of those enzymes so far. In this study, we designed and synthesized novel S-benzyl thiourea derivatives as the IDO1/TDO dual inhibitors with corroborating support by the molecular docking models. Furthermore, we demonstrated superior effect of the dual inhibitors on kynurenine production using in vitro reconstitution assay system for the tumor microenvironment expressing both IDO1 and TDO. In the syngeneic mouse model, the dual inhibitors delayed tumor progression in a lymphocyte-dependent manner.
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| Academic Significance and Societal Importance of the Research Achievements |
腫瘍の免疫寛容におけるIDO1やTDOの重要性は多く報告されているが、その制御や機序は十分に理解されていない。本研究ではS-ベンジルチオウレア誘導体をリード化合物として、活性向上だけでなくIDO1選択的、TDO選択的、IDO1/TDO二重阻害化合物をデザイン・合成し分けることに成功した。これらの化合物は医薬品開発のためのシーズとしてだけでなく、IDO1やTDOの機序解明のためのツールとして有用である。さらにドッキングモデルやMD計算を活用したアプローチや腫瘍微小環境を再構築した各種評価システムなどは、いずれもIDOやTDOを標的とした新たな免疫療法開発を目指した創薬基盤技術として意義がある。
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