PROTAC(H-PGDS)-VH

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 mol. 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.Addnl., in a DMD model using mdx mice 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.