TFC 007

Although it has been suggested that prostaglandin (PG) D(2) is involved in the pathogenesis of allergic rhinitis, whether the inhibition of hematopoietic PGD(2) synthase (H-PGDS) shows beneficial effects on allergic rhinitis has been unclear. We evaluated the effects of a selective H-PGDS inhibitor, TFC-007, on nasal symptoms on Japanese cedar pollen-induced allergic rhinitis of guinea pigs. Sensitized animals were challenged with the pollen once a week. TFC-007 (30mg/kg, p.o.) given once before a challenge almost completely suppressed PGD(2) production in the nasal tissue early and late after the challenge. Although pre-treatment did not affect the incidences of sneezing and early phase nasal blockage, late phase nasal blockage was partially but significantly attenuated; however, nasal eosinophilia was not suppressed. In contrast, when TFC-007 was given once 1.5h after the challenge, the late phase response was not affected. Collectively, PGD(2) produced by H-PGDS early after an antigen challenge can participate in the induction of late phase nasal blockage, although the mechanism may be independent of eosinophil infilatration. The strategy for H-PGDS inhibition may be beneficial for allergic rhinitis therapy.

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,PROTAC(H-PGDS)-1, was developed.PROTAC(H-PGDS)-1is composed of two ligands, TFC-007 (that binds to H-PGDS) and pomalidomide (that binds to cereblon).PROTAC(H-PGDS)-1showed potent activity in the degradation of H-PGDS protein via the ubiquitin-proteasome system and in the suppression of prostaglandin D2(PGD2) production. Notably,PROTAC(H-PGDS)-1showed sustained suppression of PGD2production after the drug removal, whereas PGD2production recovered following removal of TFC-007. Thus, the H-PGDS degrader-PROTAC(H-PGDS)-1-is expected to be useful in biological research and clinical therapies.

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 developingPROTAC(H-PGDS)-7(6), which showed potent and selective degradation activity (DC50= 17.3 pM) and potent suppression of prostaglandin D2production in KU812 cells. Additionally, in a Duchenne muscular dystrophy model usingmdxmice with cardiac hypertrophy, compound6showed 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.