Development of a Hematopoietic Prostaglandin D Synthase-Degradation Inducer.

Although hematopoietic prostaglandin D synthase (H-PGDS) is an attractive target for treatment of a variety of diseases, including allergic diseases and Duchenne muscular dystrophy, no H-PGDS inhibitors have yet been approved for treatment of these diseases. Therefore, the development of novel agents having other modes of action to modulate the activity of H-PGDS is required. In this study, a chimeric small molecule that degrades H-PGDS via the ubiquitin-proteasome system, , was developed. is composed of two ligands, TFC-007 (that binds to H-PGDS) and pomalidomide (that binds to cereblon). showed potent activity in the degradation of H-PGDS protein via the ubiquitin-proteasome system and in the suppression of prostaglandin D (PGD) production. Notably, showed sustained suppression of PGD production after the drug removal, whereas PGD production recovered following removal of TFC-007. Thus, the H-PGDS degrader--is expected to be useful in biological research and clinical therapies.