Structure-activity relationship study of PROTACs against hematopoietic prostaglandin D2 synthase

Yuki Murakami; Hinata Osawa; Takashi Kurohara; Yuta Yanase; Takahito Ito; Hidetomo Yokoo; Norihito Shibata; Mikihiko Naito; Kosuke Aritake; Yosuke Demizu

doi:10.1039/d2md00284a

Structure-activity relationship study of PROTACs against hematopoietic prostaglandin D₂ synthase

RSC Med Chem. 2022 Sep 23;13(12):1495-1503. doi: 10.1039/d2md00284a. eCollection 2022 Dec 14.

Authors

Yuki Murakami^{1

2}, Hinata Osawa^{1

3}, Takashi Kurohara¹, Yuta Yanase^{1

2}, Takahito Ito^{1

2}, Hidetomo Yokoo^{1

4}, Norihito Shibata⁵, Mikihiko Naito⁶, Kosuke Aritake⁷, Yosuke Demizu^{1

2

3}

Affiliations

¹ Division of Organic Chemistry, National Institute of Health Sciences 3-25-26, Tonomachi Kawasaki Kanagawa 210-9501 Japan demizu@nihs.go.jp.
² Graduate School of Medical Life Science, Yokohama City University 1-7-29 Yokohama Kanagawa 230-0045 Japan.
³ Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Division of Pharmaceutical Science of Okayama University 1-1-1 Tsushimanaka Kita 700-8530 Japan.
⁴ Medical Chemistry, Graduate School of Medical Science, Kyoto Prefectural University of Medicine Kyoto 606-0823 Japan.
⁵ Division of Biochemistry, National Institute of Health Sciences 3-25-26, Tonomachi Kawasaki Kanagawa 210-9501 Japan.
⁶ Laboratory of Targeted Protein Degradation, Graduate School of Pharmaceutical Sciences, The University of Tokyo Tokyo 113-0033 Japan.
⁷ Laboratory of Chemical Pharmacology, Daiichi University of Pharmacy Fukuoka 815-8511 Japan.

Abstract

Degradation of hematopoietic prostaglandin D₂ 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 (PROTAC1), 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 PROTAC1, 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 D₂ production. All compounds showed high H-PGDS degrading activities, but PROTAC(H-PGDS)-4-TAS-205 (PROTAC3) was slightly less active than the other compounds. Molecular dynamics simulations suggested that the decrease in activity of PROTAC3 may be due to the lower stability of the CRBN-PROTAC-H-PGDS ternary complex.