<p>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 <b>PROTAC(H-PGDS)-1</b>, 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 <b>PROTAC(H-PGDS)-7, </b>a new H-PGDS degrader that does not contain a linker. <b>PROTAC(H-PGDS)-7</b> showed potent and selective degradation activity (DC<sub>50</sub> = 17.3 pM), and potent suppression of prostaglandin D<sub>2</sub> (PGD<sub>2</sub>) production in KU812 cells. Additionally, in a DMD model using <i>mdx</i>mice with cardiac hypertrophy, <b>PROTAC(H-PGDS)-7</b> showed better inhibition of inflammatory cytokines than TFC-007. <b>PROTAC(H-PGDS)-7</b> is expected to be a promising candidate for the treatment of DMD and other H-PGDS-related diseases.</p>
Novel compounds for the treatment of Duchenne muscular dystrophy: emerging therapeutic agents
