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

Hematopoietic prostaglandin D synthase (H-PGDS) is an attractive target for the development of therapeutic agents for Duchenne muscular dystrophy (DMD) and other H-PGDS-related diseases. We have recently developed the H-PGDS degrader PROTAC(H-PGDS)-1, which is a chimeric molecule in which TFC-007 (that binds to H-PGDS) and pomalidomide (that binds to cereblon [CRBN]) were conjugated to the PEG5 linker. Herein, using a docking simulation of the ternary complex of the H-PGDS degrader, H-PGDS, and CRBN, we have succeeded in developing PROTAC(H-PGDS)-7, a new H-PGDS degrader that does not contain a linker. PROTAC(H-PGDS)-7 showed potent and selective degradation activity (DC₅₀ = 17.3 pM), and potent suppression of prostaglandin D₂ (PGD₂) production in KU812 cells. Additionally, in a DMD model using mdxmice with cardiac hypertrophy, PROTAC(H-PGDS)-7 showed better inhibition of inflammatory cytokines than TFC-007. PROTAC(H-PGDS)-7 is expected to be a promising candidate for the treatment of DMD and other H-PGDS-related diseases.