Discovery of a Highly Potent and Selective Degrader Targeting Hematopoietic Prostaglandin D Synthase via In Silico Design

• Published in: Journal of medicinal chemistry Vol. 64; no. 21; pp. 15868 - 15882
• Main Authors: Yokoo, Hidetomo, Shibata, Norihito, Endo, Akinori, Ito, Takahito, Yanase, Yuta, Murakami, Yuki, Fujii, Kiyonaga, Hamamura, Kengo, Saeki, Yasushi, Naito, Mikihiko, Aritake, Kosuke, Demizu, Yosuke
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 11-11-2021
• Subjects: Animals; Bone Marrow - enzymology; Cardiomegaly - metabolism; Cell Line, Tumor; Computer Simulation; Drug Discovery; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Intramolecular Oxidoreductases - antagonists & inhibitors; Intramolecular Oxidoreductases - metabolism; Ligands; Lipocalins - antagonists & inhibitors; Lipocalins - metabolism; Male; Mice; Mice, Inbred mdx; Molecular Docking Simulation; Muscular Dystrophy, Duchenne - genetics; Muscular Dystrophy, Duchenne - metabolism; Proteolysis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c01206

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.