2. Academic Validation
  3. Development of a Hematopoietic Prostaglandin D Synthase-Degradation Inducer

Development of a Hematopoietic Prostaglandin D Synthase-Degradation Inducer

  • ACS Med Chem Lett. 2021 Jan 14;12(2):236-241. doi: 10.1021/acsmedchemlett.0c00605.
Hidetomo Yokoo 1 2,  Norihito Shibata 3,  Miyako Naganuma 1,  Yuki Murakami 1 2,  Kiyonaga Fujii 4,  Takahito Ito 1,  Kosuke Aritake 5,  Mikihiko Naito 1 6,  Yosuke Demizu 1 2
Affiliations

Affiliations

  • 1 Division of Organic Chemistry, National Institute of Health Sciences, Kanagawa, Japan.
  • 2 Graduate School of Medical Life Science, Yokohama City University, Kanagawa, Japan.
  • 3 Division of Biochemistry, National Institute of Health Sciences, Kanagawa, Japan.
  • 4 Laboratory of Analytical Chemistry, Daiichi University of Pharmacy, Fukuoka, Japan.
  • 5 Laboratory of Chemical Pharmacology, Daiichi University of Pharmacy, Fukuoka, Japan.
  • 6 Laboratory of Targeted Protein Degradation, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
PMID: 33603969 DOI: 10.1021/acsmedchemlett.0c00605
Abstract

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 D2 (PGD2) production. Notably, PROTAC(H-PGDS)-1 showed sustained suppression of PGD2 production after the drug removal, whereas PGD2 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.

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