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

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.