CRBN ligand expansion for hematopoietic prostaglandin D2 synthase (H-PGDS) targeting PROTAC design and their in vitro ADME profiles

Hinata Osawa; Takashi Kurohara; Takahito Ito; Norihito Shibata; Yosuke Demizu

doi:10.1016/j.bmc.2023.117259

CRBN ligand expansion for hematopoietic prostaglandin D₂ synthase (H-PGDS) targeting PROTAC design and their in vitro ADME profiles

Bioorg Med Chem. 2023 Apr 15:84:117259. doi: 10.1016/j.bmc.2023.117259. Epub 2023 Mar 30.

Authors

Hinata Osawa¹, Takashi Kurohara², Takahito Ito³, Norihito Shibata⁴, Yosuke Demizu⁵

Affiliations

¹ Division of Organic Chemistry, National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki, Kanagawa 210-9501, Japan; Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Division of Pharmaceutical Science of Okayama University, 1-1-1 Tsushimanaka, Kita 700-8530, Japan.
² Division of Organic Chemistry, National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki, Kanagawa 210-9501, Japan.
³ Division of Organic Chemistry, National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki, Kanagawa 210-9501, Japan; Graduate School of Medical Life Science, Yokohama City University, 1-7-29, Yokohama, Kanagawa 230-0045, Japan.
⁴ Division of Biochemistry, National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki, Kanagawa 210-9501, Japan.
⁵ Division of Organic Chemistry, National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki, Kanagawa 210-9501, Japan; Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Division of Pharmaceutical Science of Okayama University, 1-1-1 Tsushimanaka, Kita 700-8530, Japan; Graduate School of Medical Life Science, Yokohama City University, 1-7-29, Yokohama, Kanagawa 230-0045, Japan. Electronic address: demizu@nihs.go.jp.

PMID: 37018877
DOI: 10.1016/j.bmc.2023.117259

Abstract

An increasing number of research reports are describing modifications of the E3 ligand, in particular, cereblon (CRBN) ligands, to improve the chemical and metabolic stabilities as well as the physical properties of PROTACs. In this study, phenyl-glutarimide (PG) and 6-fluoropomalidomide (6-F-POM), recently used as CRBN ligands for PROTAC design, were applied to hematopoietic prostaglandin D₂ synthase (H-PGDS)-targeted PROTACs. Both PROTAC-5 containing PG and PROTAC-6 containing 6-F-POM were found to have potent activities to induce H-PGDS degradation. Furthermore, we obtained in vitro ADME data on the newly designed PROTAC_S as well as our previously reported PROTACs(H-PGDS) series. Although all PROTACs(H-PGDS) are relatively stable toward metabolism, they had poor PAMPA values. Nevertheless, PROTAC-5 showed P_app values similar to TAS-205, which is in Phase 3 clinical trials, and is expected to be the key to improving the pharmacokinetics of PROTACs.

Keywords: ADME; Docking study; H-PGDS; PROTAC; Phenyl-glutarimide.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Ligands
Prostaglandins* / metabolism
Proteolysis
Proteolysis Targeting Chimera* / chemistry
Proteolysis Targeting Chimera* / pharmacology
Ubiquitin-Protein Ligases* / chemistry
Ubiquitin-Protein Ligases* / metabolism

Substances

Ligands
Prostaglandins
Ubiquitin-Protein Ligases
CRBN protein, human
prostaglandin R2 D-isomerase
Proteolysis Targeting Chimera