Development of degrader targeting proteins regulated by ubiquitination

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K22711
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0801:Pharmaceutical sciences and related fields
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Yokoo Hidetomo 京都府立医科大学, 医学(系)研究科(研究院), 客員講師 (80881424)
• Project Period (FY): 2020-09-11 – 2023-03-31
• Keywords: タンパク質分解剤 / PROTAC / ユビキチン / キメラ分子 / プロテアソーム

Outline of Final Research Achievements

Among targeted protein degradation, proteolysis targeting chimera (PROTAC) and specific and nongenetic IAP-dependent protein erasers (SNIPER) are expected to be a new drug modality that leads to ubiquitination of target proteins and their degradation by the proteasome. However, the degradation activity can change in a ubiquitin-dependent manner. In this study, we aimed to develop ubiquitin-independent degradation inducers. In this study, the development of SNIPER and PROTACs was performed against target proteins such as estrogen receptor α (ERα) and prostaglandin D synthase (H-PGDS) respectively and degraders were successfully developed. Based on the developed degraders, we designed and synthesized chimeric compounds that bind proteasome subunit ligands, and investigated their degradation activity.

Free Research Field

創薬化学

Academic Significance and Societal Importance of the Research Achievements

本研究により得られた知見は、タンパク質分解医薬品の分子設計や多様化に有用となり、開発効率化に資するための品質、有効性、安全性の確保に基づくレギュラトリーサイエンス研究の推進にも貢献しうる。