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

J Med Chem. 2021 Nov 11;64(21):15868-15882. doi: 10.1021/acs.jmedchem.1c01206. Epub 2021 Oct 15.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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


  • Enzyme Inhibitors
  • Intramolecular Oxidoreductases
  • Ligands
  • Lipocalins
  • prostaglandin R2 D-isomerase