Structure-activity relationship study of PROTACs against hematopoietic prostaglandin D synthase

• Published in: RSC medicinal chemistry Vol. 13; no. 12; pp. 1495 - 153
• Main Authors: Murakami, Yuki, Osawa, Hinata, Kurohara, Takashi, Yanase, Yuta, Ito, Takahito, Yokoo, Hidetomo, Shibata, Norihito, Naito, Mikihiko, Aritake, Kosuke, Demizu, Yosuke
• Format: Journal Article
• Published: 14.12.2022
• ISSN: 2632-8682
• DOI: 10.1039/d2md00284a

Degradation of hematopoietic prostaglandin D 2 synthase (H-PGDS) by proteolysis-targeting chimeras (PROTACs) is expected to be important in the treatment of allergic diseases and Duchenne's muscular dystrophy. We recently reported that PROTAC(H-PGDS)- 7 ( PROTAC 1 ), which is composed of H-PGDS inhibitor (TFC-007) and cereblon (CRBN) E3 ligase ligand (pomalidomide), showed potent H-PGDS degradation activity. Here, we investigated the structure-activity relationships of PROTAC 1 , focusing on the C4- or C5-conjugation of pomalidomide, in addition, the H-PGDS ligand exchanging from TFC-007 with the biaryl ether to TAS-205 with the pyrrole. Three new PROTACs were evaluated for H-PGDS affinity, H-PGDS degrading activity, and inhibition of prostaglandin D 2 production. All compounds showed high H-PGDS degrading activities, but PROTAC(H-PGDS)- 4 -TAS-205 ( PROTAC 3 ) was slightly less active than the other compounds. Molecular dynamics simulations suggested that the decrease in activity of PROTAC 3 may be due to the lower stability of the CRBN-PROTAC-H-PGDS ternary complex. SAR studies of PROTACs that target H-PGDS, focusing on the E3 ligase ligand and the H-PGDS ligand, are described.