1. Discovery of a Highly Potent and Selective Degrader Targeting Hematopoietic Prostaglandin D Synthase via In Silico Design
- Author
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Norihito Shibata, Mikihiko Naito, Takahito Ito, Yuta Yanase, Yasushi Saeki, Kengo Hamamura, Kiyonaga Fujii, Hidetomo Yokoo, Yosuke Demizu, Yuki Murakami, Akinori Endo, and Kosuke Aritake
- Subjects
Male ,In silico ,Cardiomegaly ,Protein degradation ,Ligands ,Mice ,chemistry.chemical_compound ,Bone Marrow ,Cell Line, Tumor ,Drug Discovery ,Animals ,Humans ,Computer Simulation ,Enzyme Inhibitors ,Drug discovery ,Cereblon ,Ligand (biochemistry) ,Lipocalins ,Cell biology ,Intramolecular Oxidoreductases ,Molecular Docking Simulation ,Muscular Dystrophy, Duchenne ,chemistry ,Docking (molecular) ,Proteolysis ,Mice, Inbred mdx ,Molecular Medicine ,Target protein ,Prostaglandin D2 - Abstract
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.
- Published
- 2021
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