1. Development of a Hematopoietic Prostaglandin D Synthase-Degradation Inducer
- Author
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Kosuke Aritake, Yosuke Demizu, Yuki Murakami, Miyako Naganuma, Hidetomo Yokoo, Norihito Shibata, Kiyonaga Fujii, Mikihiko Naito, and Takahito Ito
- Subjects
Drug ,010405 organic chemistry ,Chemistry ,media_common.quotation_subject ,Cereblon ,Duchenne muscular dystrophy ,Organic Chemistry ,Pharmacology ,Pomalidomide ,medicine.disease ,01 natural sciences ,Biochemistry ,Small molecule ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,Proteasome ,Drug Discovery ,medicine ,Inducer ,Prostaglandin D2 ,medicine.drug ,media_common - Abstract
[Image: see text] 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)-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 D(2) (PGD(2)) production. Notably, PROTAC(H-PGDS)-1 showed sustained suppression of PGD(2) production after the drug removal, whereas PGD(2) production 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.
- Published
- 2021
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