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submitted on 02.10.2020 and posted on 05.10.2020by Hidetomo Yokoo, Norihito Shibata, Miyako Naganuma, Kiyonaga Fujii, Takahito Ito, Kosuke Aritake, Mikihiko Naito, Yosuke Demizu
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 mode of actions 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)-1 is composed of two ligands, TFC-007 (that
binds to H-PGDS) and pomalidomide (that binds to cereblon). PROTAC(H-PGDS)-1
showed 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)-1 was slightly more effective in the
suppression of PGD2 production than the known inhibitor, TFC-007. Thus, the H-PGDS
degrader—PROTAC(H-PGDS)-1—is expected to be useful in biological research and