Dehydrocholesterol Reductase 24 (DHCR24): Medicinal Chemistry, Pharmacology and Novel Therapeutic Options

Title:Dehydrocholesterol Reductase 24 (DHCR24): Medicinal Chemistry, Pharmacology and Novel Therapeutic Options

Volume: 29 Issue: 23

Author(s): Christoph Müller, Emily Hank, Martin Giera and Franz Bracher*

Affiliation:

• Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians University Munich, Munich, Germany

Keywords: Dehydrocholesterol reductase 24, enzyme inhibitor, desmosterol, liver X receptor, inflammation resolution, nonalcoholic steatohepatitis.

Abstract:

During the last decade, the understanding of the biological functions of cholesterol biosynthesis intermediates has changed significantly. Particularly, the enzyme sterol dehydrocholesterol reductase 24 (DHCR24) has taken center stage as a potential drug target. Inhibition of DHCR24 leads to accumulation of the endogenous, biologically active metabolite cholesta-5,24-dien-3β-ol (desmosterol). Desmosterol is an endogenous agonist of the liver X receptor (LXR). LXR is a master regulator of lipid metabolism and, as such, is involved in numerous pathophysiological processes such as inflammation, atherosclerosis, cancer, diabetes mellitus (DM), multiple sclerosis (MS), nonalcoholic steatohepatitis (NASH), and the progression of viral infections. Up to now, selective pharmacological targeting of LXR without activating the sterol-response element binding proteins (SREBP) and thereby boosting endogenous lipid biosynthesis has not been achieved. In turn, no selective LXR receptor agonists leveraging its beneficial activation have yet reached the clinic. Therefore, using potent and selective inhibitors of DHCR24 leading to an accumulation of endogenous desmosterol is a promising alternative strategy for the selective activation of LXR.

Here we summarize the present landscape of novel lead structures for targeting DHCR24, covering steroidal enzyme inhibitors (e.g., 20,25-diazacholesterol, SH42) as well as nonsteroidal scaffolds (e.g., amiodarone, triparanol). Further, we explain the molecular mechanisms of DHCR24 inhibition/LXR activation, discuss possible therapeutic applications, and underpin why DHCR24 is an upcoming promising drug target.

Cite this article as:

Müller Christoph , Hank Emily , Giera Martin and Bracher Franz *, Dehydrocholesterol Reductase 24 (DHCR24): Medicinal Chemistry, Pharmacology and Novel Therapeutic Options, Current Medicinal Chemistry 2022; 29 (23) . https://dx.doi.org/10.2174/0929867328666211115121832