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.
journal_name
Bioorg Med Chemjournal_title
Bioorganic & medicinal chemistryauthors
Sagimori I,Yoshioka H,Hashimoto Y,Ohgane Kdoi
10.1016/j.bmc.2019.115298subject
Has Abstractpub_date
2020-02-01 00:00:00pages
115298issue
3eissn
0968-0896issn
1464-3391pii
S0968-0896(19)31881-4journal_volume
28pub_type
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