Development of Agonist-Based PROTACs Targeting Liver X Receptor

Frontiers in Chemistry

Takao Inoue¹  Nobumichi Ohoka¹  Hidetomo Yokoo²  Kanako Nemoto²  Genichiro Tsuji²  Hiroshi Matsufuji³  Takashi Ohtsuki³  Hanqiao Xu³  Yosuke Demizu⁴  Mikihiko Naito⁵ 

[1] Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, Kanagawa, Japan;Division of Organic Chemistry, National Institute of Health Sciences, Kanagawa, Japan;Food Bioscience and Biotechnology, College of Bioresource Sciences, Nihon University, Fujisawa, Japan;Graduate School of Medical Life Science, Yokohama City University, Kanagawa, Japan;Laboratory of Targeted Protein Degradation, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan;

关键词: liver X receptor;    PROTAC;    ubiquitin-proteasome system;    von Hippel-Lindau;    protein degradation;   

DOI  :  10.3389/fchem.2021.674967

来源: DOAJ

【 摘 要 】

Liver X receptors (LXRs) belong to the nuclear hormone receptor superfamily and function as ligand-dependent transcription factors that regulate cholesterol homeostasis, lipid homeostasis, and immune responses. LXR antagonists are promising treatments for hypercholesterolemia and diabetes. However, effective LXR antagonists and inhibitors are yet to be developed. Thus, we aimed to develop LXR degraders (proteolysis targeting chimeras PROTACs against LXR) as a complementary strategy to provide a similar effect to LXR inhibition. In this study, we report the development of GW3965-PEG5-VH032 (3), a PROTAC capable of effectively degrading LXRβ protein. Compound 3 induced the ubiquitin-proteasome system-dependent degradation of the LXRβ protein, which requires VHL E3 ligase. We hope that PROTACs targeting LXR proteins will become novel therapeutic agents for LXR-related diseases.

【 授权许可】

Unknown