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

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

Bioorganic & medicinal chemistry (2020-01-07)
Ikuya Sagimori, Hiromasa Yoshioka, Yuichi Hashimoto, Kenji Ohgane
ABSTRACT

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.

MATERIALS
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Sigma-Aldrich
22(R)-Hydroxycholesterol, ≥98%
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Sigma-Aldrich
25-Hydroxycholesterol, ≥98%
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Sigma-Aldrich
22(S)-Hydroxycholesterol
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Sigma-Aldrich
TAK-475, ≥98% (HPLC)
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