Development of a Hematopoietic Prostaglandin D Synthase-Degradation Inducer

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 agent...

Full description

Saved in:
Bibliographic Details
Published in:ACS medicinal chemistry letters 2021-02, Vol.12 (2), p.236-241
Main Authors: Yokoo, Hidetomo, Shibata, Norihito, Naganuma, Miyako, Murakami, Yuki, Fujii, Kiyonaga, Ito, Takahito, Aritake, Kosuke, Naito, Mikihiko, Demizu, Yosuke
Format: Article
Language:English
Subjects:
Letter
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.0c00605