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

TITLE=Development of Agonist-Based PROTACs Targeting Liver X Receptor

JOURNAL=Frontiers in Chemistry

VOLUME=9

YEAR=2021

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2021.674967

DOI=10.3389/fchem.2021.674967

ISSN=2296-2646

ABSTRACT=<p>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 (<bold>3</bold>), a PROTAC capable of effectively degrading LXRβ protein. Compound <bold>3</bold> 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.</p>