2023 Fiscal Year Final Research Report
Development of novel PROTACs that activates antitumor immunity
Project/Area Number |
21K15251
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Research Category |
Grant-in-Aid for Early-Career Scientists
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Allocation Type | Multi-year Fund |
Review Section |
Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
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Research Institution | Hokkaido University |
Principal Investigator |
Kitai Yuichi 北海道大学, 薬学研究院, 助教 (90756165)
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Project Period (FY) |
2021-04-01 – 2024-03-31
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Keywords | 自然免疫 / DAMP / PROTAC |
Outline of Final Research Achievements |
Damage-associated molecular patterns (DAMPs) are secreted from the damaged or dying cells and activate innate immune siginaling via pattern-recognition receptors such as Toll-like receptors and cGAS. Our previous studies showed that topotecan and SN-38, a topoisomerase I (TOP1) inhibitor, binds to ribosomal protein RPL15 and induces the secretion of immunostimulatory DNA as DAMP from cancer cells which activate cGAS-STING signaling in dendritic cells. Here, we syhthesized SN-38-comjugated pomalidomide (SN38-PROTAC) and showed that SN38-PROTAC selectively degraded RPL15 protein dependent on ubiquitin-proteasome pathway but not TOP1. SN38-PROTAC treatment induced DAMP secretion from cancer cells which activated cGAS-STING signaling in denderitic cells, but cytotoxicity of SN38-PROTAC was 100-fold lower than SN-38 in MCF7 cells. SN38-PROTAC acts as an enhancer for anti-PD-1 therapy in tumor-bearing mouse model.
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Free Research Field |
免疫学
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Academic Significance and Societal Importance of the Research Achievements |
本研究はRPL15に対する特異的な阻害剤であるSN38-PROTACを初めて開発したことと、SN38-PROTACが抗PD-1抗体などの免疫チェックポイント阻害剤の治療効果を改善できる可能性があることを示したという2点において、学術的および社会的な意義があると考えられる。
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