Yokoo Hidetomo, Shibata Norihito, Naganuma Miyako, Murakami Yuki, Fujii Kiyonaga, Ito Takahito, Aritake Kosuke, Naito Mikihiko, Demizu Yosuke
Division of Organic Chemistry, National Institute of Health Sciences, Kanagawa, Japan.
Graduate School of Medical Life Science, Yokohama City University, Kanagawa, Japan.
ACS Med Chem Lett. 2021 Jan 14;12(2):236-241. doi: 10.1021/acsmedchemlett.0c00605. eCollection 2021 Feb 11.
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, , was developed. is composed of two ligands, TFC-007 (that binds to H-PGDS) and pomalidomide (that binds to cereblon). showed potent activity in the degradation of H-PGDS protein via the ubiquitin-proteasome system and in the suppression of prostaglandin D (PGD) production. Notably, showed sustained suppression of PGD production after the drug removal, whereas PGD production recovered following removal of TFC-007. Thus, the H-PGDS degrader--is expected to be useful in biological research and clinical therapies.
尽管造血前列腺素D合成酶（H-PGDS）是治疗多种疾病（包括过敏性疾病和杜氏肌营养不良症）的一个有吸引力的靶点，但尚未有H-PGDS抑制剂被批准用于治疗这些疾病。因此，需要开发具有其他作用模式来调节H-PGDS活性的新型药物。在本研究中，开发了一种通过泛素-蛋白酶体系统降解H-PGDS的嵌合小分子。它由两种配体组成，TFC-007（与H-PGDS结合）和泊马度胺（与脑啡肽结合）。在通过泛素-蛋白酶体系统降解H-PGDS蛋白以及抑制前列腺素D（PGD）产生方面表现出强大的活性。值得注意的是，在药物去除后仍能持续抑制PGD的产生，而在去除TFC-007后PGD的产生会恢复。因此，H-PGDS降解剂有望在生物学研究和临床治疗中发挥作用。
