Development of Agonist-Based PROTACs Targeting Liver X Receptor

Hanqiao Xu; Nobumichi Ohoka; Hidetomo Yokoo; Kanako Nemoto; Takashi Ohtsuki; Hiroshi Matsufuji; Mikihiko Naito; Takao Inoue; Genichiro Tsuji; Yosuke Demizu

doi:10.3389/fchem.2021.674967

Development of Agonist-Based PROTACs Targeting Liver X Receptor

Front Chem. 2021 May 26:9:674967. doi: 10.3389/fchem.2021.674967. eCollection 2021.

Authors

Affiliations

¹ Division of Organic Chemistry, National Institute of Health Sciences, Kanagawa, Japan.
² Food Bioscience and Biotechnology, College of Bioresource Sciences, Nihon University, Fujisawa, Japan.
³ Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, Kanagawa, Japan.
⁴ Laboratory of Targeted Protein Degradation, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
⁵ Graduate School of Medical Life Science, Yokohama City University, Kanagawa, Japan.

Abstract

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.

Keywords: PROTAC; liver X receptor; protein degradation; ubiquitin-proteasome system; von Hippel-Lindau.