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論文
- タイトル
- タイトル（英）
- Discovery of a Highly Potent and Selective Degrader Targeting Hematopoietic Prostaglandin D Synthase via In Silico Design.
- 参照URL
- https://researchmap.jp/myportal_saeki-ys/published_papers/37644303
- 著者
- 著者（英）
- Hidetomo Yokoo,Norihito Shibata,Akinori Endo,Takahito Ito,Yuta Yanase,Yuki Murakami,Kiyonaga Fujii,Kengo Hamamura,Yasushi Saeki,Mikihiko Naito,Kosuke Aritake,Yosuke Demizu
- 担当区分
- 概要
- 概要（英）
- Targeted protein degradation by proteolysis-targeting chimera (PROTAC) is one of the exciting modalities for drug discovery and biological discovery. It is important to select an appropriate linker, an E3 ligase ligand, and a target protein ligand in the development; however, it is necessary to synthesize a large number of PROTACs through trial and error. Herein, using a docking simulation of the ternary complex of a hematopoietic prostaglandin D synthase (H-PGDS) degrader, H-PGDS, and cereblon, we have succeeded in developing PROTAC(H-PGDS)-7 (6), which showed potent and selective degradation activity (DC50 = 17.3 pM) and potent suppression of prostaglandin D2 production in KU812 cells. Additionally, in a Duchenne muscular dystrophy model using mdx mice with cardiac hypertrophy, compound 6 showed better inhibition of inflammatory cytokines than a potent H-PGDS inhibitor TFC-007. Thus, our results demonstrated that in silico simulation would be useful for the rational development of PROTACs.
- 出版者・発行元
- 出版者・発行元（英）
- 誌名
- 誌名（英）
- Journal of medicinal chemistry
- 巻
- 64
- 号
- 21
- 開始ページ
- 15868
- 終了ページ
- 15882
- 出版年月
- 2021年11月11日
- 査読の有無
- 招待の有無
- 掲載種別
- 研究論文（学術雑誌）
- ISSN
- DOI URL
- https://doi.org/10.1021/acs.jmedchem.1c01206
- 共同研究・競争的資金等の研究課題