Dehydrocholesterol Reductase 24 (DHCR24): Medicinal Chemistry, Pharmacology and Novel Therapeutic Options
Abstract
Over the past decade, our understanding of cholesterol biosynthesis intermediates and their biological roles has evolved considerably. Among these intermediates, the enzyme sterol dehydrocholesterol reductase 24 (DHCR24) has emerged as a promising drug target. Inhibiting DHCR24 leads to the buildup of cholesta-5,24-dien-3β-ol (desmosterol), an endogenous metabolite that acts as an agonist for the liver X receptor (LXR). LXR plays a crucial role in regulating lipid metabolism and is implicated in various pathophysiological conditions such as inflammation, atherosclerosis, cancer, diabetes mellitus, multiple sclerosis, nonalcoholic steatohepatitis, and the progression of viral infections.
To date, achieving selective pharmacological targeting of LXR without simultaneously activating sterol-response element binding proteins (SREBP)—which would otherwise increase endogenous lipid biosynthesis—has been challenging. Consequently, no selective LXR receptor agonists that harness its beneficial effects have yet been approved for clinical use. Thus, employing potent and selective DHCR24 inhibitors to increase endogenous desmosterol levels represents a promising strategy for targeted LXR activation.
In this review, we provide an overview of current lead structures for targeting DHCR24, including both steroidal enzyme inhibitors (e.g., 20,25-diazacholesterol, SH42) and nonsteroidal compounds (e.g., amiodarone, triparanol). We also detail the molecular mechanisms by which DHCR24 inhibition leads to LXR activation, explore potential therapeutic applications, and highlight why DHCR24 is a promising target for drug Triparanol development.