Development of degrader targeting proteins regulated by ubiquitination
| Project/Area Number |
20K22711
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| Research Category |
Grant-in-Aid for Research Activity Start-up
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| Allocation Type | Multi-year Fund |
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| Review Section |
0801:Pharmaceutical sciences and related fields
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| Research Institution | Kyoto Prefectural University of Medicine |
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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)
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| Project Period (FY) |
2020-09-11 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| 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 / 直接的分解 |
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| Outline of Research at the Start |
新たな創薬手法として期待されているタンパク質分解誘導剤は、標的タンパク質のユビキチン化、プロテアソームによる分解を導く。しかしユビキチン化が起きない場合や、分解以外のシグナルによる副作用が課題である。このため本研究では、標的タンパク質のリガンドとプロテアソーム結合部位をリンカーでつなぐことで、プロテアソームを標的タンパク質に直接近づける、新しい分解誘導剤を開発する。特に、プロテアソームに結合する小分子を用いることで、細胞膜を透過しやすい分子を開発し、既存の技術では分解が難しいタンパク質へ応用する。
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| 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.
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| 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。
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Report
(4 results)
Research Products
(40 results)
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[Presentation] Specific degrader of hematopoietic prostaglandin D synthase prevented the progression of dilated cardiomyopathy in Duchenne muscular dystrophy2022
Author(s)
Maeyama, Y., Hosokawa, Y., Hamamura, K., Yokoo, H., Shibata, N., Naito,M.,Demizu,Y.,Aritake,K.
Organizer
第95回日本薬理学会年会
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