Development of a Hematopoietic Prostaglandin D Synthase-Degradation Inducer

Hidetomo Yokoo; Norihito Shibata; Miyako Naganuma; Yuki Murakami; Kiyonaga Fujii; Takahito Ito; Kosuke Aritake; Mikihiko Naito; Yosuke Demizu

doi:10.1021/acsmedchemlett.0c00605

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. eCollection 2021 Feb 11.

Authors

Hidetomo Yokoo^{1

2}, Norihito Shibata³, Miyako Naganuma¹, Yuki Murakami^{1

2}, Kiyonaga Fujii⁴, Takahito Ito¹, Kosuke Aritake⁵, Mikihiko Naito^{1

6}, Yosuke Demizu^{1

2}

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.

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.