Targeting REV-ERBα for therapeutic purposes: promises and challenges

Abstract

REV-ERBα (NR1D1) is a circadian clock component that functions as a transcriptional repressor. Due to its role in direct modulation of metabolic genes, REV-ERBα is regarded as an integrator of cell metabolism with circadian clock. Accordingly, REV-ERBα is first proposed as a drug target for treating sleep disorders and metabolic syndromes (e.g., dyslipidaemia, hyperglycaemia and obesity). Recent years of studies uncover a rather broad role of REV-ERBα in pathological conditions including local inflammatory diseases, heart failure and cancers. Moreover, REV-ERBα is involved in regulation of circadian drug metabolism that has implications in chronopharmacology. In the meantime, recent years have witnessed discovery of an array of new REV-ERBα ligands most of which have pharmacological activities in vivo. In this article, we review the regulatory role of REV-ERBα in various types of diseases and discuss the underlying mechanisms. We also describe the newly discovered ligands and the old ones together with their targeting potential. Despite well-established pharmacological effects of REV-ERBα ligands in animals (preclinical studies), no progress has been made regarding their translation to clinical trials. This implies certain challenges associated with drug development of REV-ERBα ligands. In particular, we discuss the potential challenges related to drug safety (or adverse effects) and bioavailability. For new drug development, it is advocated that REV-ERBα should be targeted to treat local diseases and a targeting drug should be locally distributed, avoiding the adverse effects on other tissues.

Figure 1

REV‑ERBα in circadian clock system. (A) Schematic diagram for molecular clock machinery. Mammalian molecular clock consists of three interlocked auto-regulatory feedback loops. The three loops are attained through PERs/CRYs (black lines), REV-ERBs/RORs (green lines) and DBP/E4BP4 (blue lines), respectively. (B) Circadian mRNA expression patterns of clock genes in mice. (C) General patterns for regulation of target genes by REV‑ERBα. REV‑ERBα directly regulates transcription of target genes via single RORE (i), RevDR2 (ii) or two adjacent ROREs (iii), and indirectly regulates gene transcription via other transcription factors (TFs) (iv).

Figure 2

REV‑ERBα controlled genes and pathways. (A) Circos plot of differentially expressed genes between Rev-erbα^-/-and wild-type mice, showing a disturbance in genome-wide gene expression. In the Circos plot, the outermost circle depicts the ideograms of each chromosome; the second circle represents gene expression levels; the third circle shows the distribution of the up-regulated genes; and the fourth circle shows the distribution of the down-regulated genes. (B) KEGG pathway analysis of Rev-erbα-induced differentially expressed genes in mouse liver (top 20 pathways are shown).

Figure 3

Functions of REV‑ERBα in various tissues. REV‑ERBα regulates clock-controlled genes (CCGs) to affect disease development in a tissue-specific manner. REV‑ERBα directly regulates target genes or indirectly regulates gene transcription via other transcription factors (e.g., E4BP4).

Figure 4

REV‑ERBα regulates immune genes in macrophages and T_H17 cells. (A) In macrophages, a variety of immune genes (i.e., P65, Nlrp3, IL-1β, TLR4, IL-6, Ccl2, Mmp9 and Cx3cr1) are controlled by REV-ERBα. (B) REV-ERBα negatively regulates T_H17 cell development by competing with RORgt at the RORE of Il-17a. An additional mechanism involves REV-ERBα-mediated repression of RORgt.

Figure 5

REV‑ERBα is involved in chronopharmacokinetics and chronotoxicity via regulating drug-metabolizing enzymes (DMEs). REV-ERBα directly or indirectly regulates clock-controlled genes (CCGs) involved in drug metabolism. The DMEs consists of “phase I enzymes” and “phase II enzymes”. Circadian expressions of these genes result in dosing time-dependent pharmacokinetics and therefore in time-varying drug effects (toxicity and efficacy). For instance, Cyp2b10 (a Rev-erbα target) metabolizes cyclophosphamide (CPA) to its toxic (4-hydroxylated) metabolite 4-OH-CPA. The CPA chronotoxicity is associated with time-varying generation of 4-OH-CPA caused by diurnal Cyp2b10 expression.

Figure 6

Historical timeline for discovery of REV-ERBs and development of representative ligands from 1989 to 2019. Chemical structures of all ligands except SR12418 (unavailable) are shown in the figure.