Luciferase-based HMG-CoA reductase degradation assay for activity and selectivity profiling of oxy(lano)sterols

Ikuya Sagimori, Hiromasa Yoshioka, Yuichi Hashimoto, Kenji Ohgane

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1 Citation (Scopus)


HMG-CoA reductase (HMGCR) is the rate-limiting enzyme in the cholesterol biosynthetic pathway, and is the target of cholesterol-lowering drugs, statins. Previous studies have demonstrated that the enzyme activity is regulated by sterol-induced degradation in addition to transcriptional regulation through sterol-regulatory-element-binding proteins (SREBPs). While 25-hydroxycholesterol induces both HMGCR degradation and SREBP inhibition in a nonselective manner, lanosterol selectively induces HMGCR degradation. Here, to clarify the structural determinants of selectivity for the two activities, we established a luciferase-based assay monitoring HMGCR degradation and used it to profile the structure-activity/selectivity relationships of oxysterols and (oxy)lanosterols. We identified several sterols that selectively induce HMGCR degradation and one sterol, 25-hydroxycholest-4-en-3-one, that selectively inhibits the SREBP pathway. These results should be helpful in designing more potent and selective HMGCR degraders.

Original languageEnglish
Article number115298
JournalBioorganic and Medicinal Chemistry
Issue number3
Publication statusPublished - 1 Feb 2020


  • Degradation
  • HMG-CoA reductase
  • Lanosterols
  • Luciferase
  • Oxysterols

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