Development of ADC with novel anticancer drug release system triggered by peptide cyclization reaction

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K15253
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
• Research Institution: The University of Tokushima
• Principal Investigator: DENDA Masaya 徳島大学, 大学院医歯薬学研究部(薬学域), 助教 (00813891)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Keywords: ペプチド環化反応 / ADC / alpha-Amanitin / N-Sアシル基転移反応

Outline of Final Research Achievements

Antibody-drug conjugates (ADCs) are attracting attention as new anticancer agents. In this study, we aimed to develop an active anti-cancer drug release system triggered by peptide cyclization reaction to suppress non-selective release of anti-cancer drugs, which is a problem of ADCs. In this study, we focused on Amanitin, a bicyclic cyclic peptide, as an anticancer drug to be loaded on ADCs. First, a novel synthetic method for amanitin was established. Furthermore, we demonstrated that the release of peptides can be triggered by the formation of cyclic peptides by using a probe that converts to thioesters by N-S acyl-transfer reaction under acidic conditions.

Free Research Field

ペプチド化学

Academic Significance and Societal Importance of the Research Achievements

抗体-薬物複合体（ADC）は、新たな抗がん剤として非常に有用である。しかしながら抗体-薬物間リンカーの非選択的な切断による薬物放出は、全身性副作用発現などに関与する非常に重大な問題点である。本研究で開発を目指してきた、がん細胞内選択的なペプチド環化反応による活性化とこれをトリガーとする活性型ペプチド性抗がん剤放出システムは、従来のADCが有する上述問題点を解決する戦略となり得ることから、社会的意義は非常に大きいものである。