期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 64, 期 21, 页码 15868-15882出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c01206
关键词
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资金
- Japan Agency for Medical Research and Development [21ak0101073j0905]
- Japan Society for the Promotion of Science
- Ministry of Education, Culture, Sports, Science and Technology (JSPS/MEXT KAKENHI) [JP20K22711, JP18K07311, JP20K06568, JP17K08385, 21K05320, JP18H05498, JP18H05502]
- Takeda Science Foundation
- Naito Foundation
- Sumitomo Foundation
- Novartis Foundation (Japan) for the Promotion of Science
- Japan Foundation of Applied Enzymology
- Kobayashi Foundation for Cancer Research
- Foundation for Promotion of Cancer Research in Japan
- High-Quality Protein Crystal Growth Experiment on JEM, Japan Aerospace Exploration Agency (JAXA)
- Grants-in-Aid for Scientific Research [21K05320] Funding Source: KAKEN
PROTAC, an important modality for targeted protein degradation, requires careful selection of appropriate linker, E3 ligase ligand, and target protein ligand for successful development. In silico simulation can be a useful tool for rational development of PROTACs.
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 D-2 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.
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