Medicinal chemistry on cyclic dinucleotides as immunotherapeutic agents.

2018 Fiscal Year Final Research Report

• Project/Area Number: 17K15481
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Drug development chemistry
• Research Institution: The University of Tokushima
• Principal Investigator: TARASHIMA Noriko 徳島大学, 大学院医歯薬学研究部(薬学域), 助教 (90755183)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Keywords: 環状ジヌクレオチド / がん免疫療法 / 化学修飾核酸

Outline of Final Research Achievements

Recently, cyclic dinucleotides (CDNs) are fascinating molecules in drug discovery, because CDNs were identified as the ligands of stimulator of interferon genes (STING), which mediates innate immune responses. However, there are some issues to be solved for the development of drug candidates based on the CDNs themselves. First, the penetration of cell membrane is hampered by the negatively-charged phosphate groups of CDNs. Second, cytoplasmic phosphodiesterases can easily break the phosphodiester bond of CDNs. Therefore, in this study, we explored explore novel compounds to develop a CDN-based drugs from two strategies: 1) prodrug development, and 2) creation of cyclic dipeptide-type analogs without negatively-charged phosphate groups.

Free Research Field

核酸創薬化学

Academic Significance and Societal Importance of the Research Achievements

現在，がん免疫療法薬の中心は，PD-1などのT細胞免疫チェックポイント分子に対するモノクローナル抗体 (免疫チェックポイント阻害薬/2018年ノーベル医学生理学賞) であるが，高い治療効果を発揮する反面，その高額な薬剤費ゆえに，医療費破綻の懸念が大きな社会問題となっている．この現状を打破するため，本研究では，がん免疫賦活作用を有することが知られている環状ジヌクレオチド類をシードとした創薬化学研究を実施し，いくつかの有用なアナログを獲得することに成功した．