The Transcriptional Repressor REV-ERB As a Novel Target for Disease

Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com The transcriptional repressor REV-ERB as a novel target for disease Amaia Uriz-Huarte a, Amrita Date a, Heather Ang b, Simak Alic, Hugh J. M. Brady b and Matthew J. Fuchter a* a Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, White City Campus, Wood Lane, London W12 0BZ, UK b Department of Life Sciences, Imperial College London, South Kensington, London, SW7 2AZ, UK c Division of Cancer, Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK Corresponding author. Tel.: +44 (0)20 7594 5815; e-mail: [email protected] ARTICLE INFO ABSTRACT Article history: REV-ERB is a member of the nuclear receptor superfamily of transcription factors involved in the Received regulation of many physiological processes, from circadian rhythm, to immune function and Revised metabolism. Accordingly, REV-ERB has been considered as a promising, but difficult drug target Accepted for the treatment of numerous diseases. Here, we concisely review current understanding of the Available online function of REV-ERB, modulation by endogenous factors and synthetic ligands, and the involvement of REV-ERB in select human diseases. Particular focus is placed on the medicinal chemistry of synthetic REV-ERB ligands, which demonstrates the need for higher quality ligands to aid in robust validation of this exciting target. Keywords: REV-ERB, transcription factor, drug development 2009 Elsevier Ltd. All rights reserved. The misregulation of transcription plays a key role in the inherently druggable and have long been recognised as drug targets development and maintenance of many human diseases. Direct for new medicines.1,4 There are a large number of approved drugs regulators of transcriptional events are therefore often considered across many disease indications that target nuclear receptors; from as interesting drug targets. Despite this, many such transcription ligands of the estrogen receptor (for example, Tamoxifen) for the factors are labelled as ‘undruggable’1 for a range of reasons treatment of breast cancer, to ligands of the glucocorticoid receptor grounded in the logistics of small molecule drug discovery. These (for example, Dexamethasone) for anti-inflammatory usage. factors range from intrinsic disorder at the protein level, to lack of Nonetheless, there are many more opportunities for the therapeutic suitable binding pockets for small molecule ligands. While such an exploitation of the nuclear receptor superfamily. undruggable designation is driving further innovation in medicinal REV-ERB is a member of the nuclear receptor family consisting chemistry,2 it is clearly false to label all transcription factors as of two similar proteins: REV-ERBα5 and REV-ERBβ.6 The name such. Nuclear receptors are transcription factors that are REV-ERB is derived from “reverse-ERB”, since the NR1D1 gene responsible for sensing molecules (such as hormones) and, in that codes for REV-ERBα was mapped on the antisense DNA response, directly regulating the expression of specific subsets of strand of the ERBA proto-oncogene (THRA, thyroid hormone genes.3 By virtue of their control by small molecules, they are receptor-α).5 The closely related NR1D2 gene encodes for the other Figure 1. On the left, general structure of nuclear receptors and the structure of REV-ERB, lacking activatory function 2 (AF2) in the C-terminal domain. The values reported represent % in amino acid identity for each domain comparing REV-ERBα and β. The N-terminal domains were too variable for comparison. Sequences were obtained from Uniprot. Query covers and amino acid identity were calculated via BLASTP algorithm using NCBI BLAST webtool. On the right, the mechanism of transcriptional regulation by REV-ERB. REV-ERB binds as a dimer to the RORE region of target genes, driving recruitment of NCOR1, followed by recruitment of HDAC3, which deacetylates histone tails and leads to chromatin condensation and transcription repression of target genes. isoform, REV-ERBβ. REV-ERBα and REV-ERBß share almost detailed discussion, readers are directed to several excellent complete identity in their DNA binding domains (DBD), while reviews on the topic.8,11,16 only 71% amino acid sequence identity in their ligand binding Shortly after its discovery in 1989,5 REV-ERB was seen to domains (LBD) (Figure 1). Moreover, they show similar fluctuate in a circadian manner, suggesting a role in circadian expression patterns within tissues.7 Potential partial redundancy rhythm; a 24 h oscillatory cycle that regulates multiple biological has been shown in knock out mice, where the presence of REV- processes. The direct role of REV-ERB in the circadian cycle is ERBβ can compensate the loss of REV-ERBα, at least in certain now well established, with other essential regulators being tissues.8 rhythmically regulated by REV-ERB in tightly controlled feedback As is the case for all nuclear receptors, DNA binding by REV- loops (Figure 2).17 The dimer formed by circadian regulators ERBα/β is mediated by two zinc fingers and is responsible for CLOCK or NPAS2, together with BMAL1 (also known as recognising and binding to specific genomic regions of target ARNTL) activates transcription of CRY, PER, REV-ERB and ROR. genes.9 Unlike most other nuclear receptors however, REV-ERBs Once CRY and PER reach threshold levels, the CRY/PER dimer lack the carboxy terminal activation function 2 (AF2) at the C- inhibits the action of BMAL1/CLOCK and BMAL1/NPAS2, terminal end of the LBD (Figure 1 left).10 Because the AF2 region leading as well to reduced levels of CRY and PER themselves. On recognises co-activator protein partners responsible for the other hand, REV-ERB acts as a repressor of BMAL1, CLOCK transcriptional activation, the REV-ERBs are thought to be unable and NPAS2 expression, while ROR binds competitively to the to activate transcription. Instead, they act as constitutive repressors RORE region to activate their transcription.18,19 of transcription through binding via the DBD to the ROR response Given the role of REV-ERB in this tightly regulated system, the element DNA sequence (RORE). This binding site creates an targeting of REV-ERB holds promise to modulate many of the interesting dynamic interplay with the retinoic acid receptor- biological processes dependent on the circadian cycle. Metabolism related orphan receptor (ROR), which binds to many of the same is well known to be under circadian control,20,21 where REV-ERB target genes, but results in transcriptional activation.11 Two REV- regulates lipid22 and glucose metabolism,23,24 as well as adipocyte ERB molecules, usually present as a dimer, compete with ROR for differentiation,25–27 making it a target for the treatment of metabolic the binding to the RORE region.8 Their successful binding to the diseases. In this context, the use of REV-ERB activating agonists DBD results in the recruitment of a nuclear receptor corepressor was reported to lead to downregulation of expression of the (NCOR1). The NCOR1 complex then recruits histone deacetylase lipogenic gene Srebf1 and the fatty acid synthase gene Fasn, as 3 (HDAC3), which leads to chromatin condensation and well as elevated transcriptional levels of the fatty acid transport transcription repression through histone deacetylation (Figure gene Fatp1.21 The apolipoprotein A1 (ApoA1) and apolipoprotein 1).12,13 C3 (ApoC3) genes also play a major role in cholesterol metabolism REV-ERB has been implicated as a potential target in a range and their repression by REV-ERB is yet another mechanism of of diseases. Whether activation or inhibition of the repressive regulation of lipid metabolism mediated by this transcription action of REV-ERB is required depends on the disease in question, factor.22 Similarly, conversion of cholesterol to bile acids, which as outlined below. Furthermore, as has previously been identified facilitate digestion of dietary fats and oils, is achieved via for other nuclear receptors, some ligands show opposing effects in downregulation of gene expression of the transcription factor different cell types, which further complicates analysis and target E4BP4 in the liver and the signalling molecule SHP by REV- validation.14,15 Therefore, high quality small molecule activators ERB.28 Overall, the enhancement of REV-ERB activity by and inhibitors of REV-ERB function (vide infra) are both useful synthetic agonist compounds has been reported to lead to weight tools and would potentially be applicable in different disease loss, reduced cholesterol and improved metabolic functions.21 contexts. A brief discussion of select examples that showcase the Furthermore, high levels of REV-ERB have been correlated with potential of REV-ERB as a drug target are given below. For more increased insulin secretion and reduced glucose concentration, highlighting the potential use of REV-ERB agonists for the treatment of type 2 diabetes.24 Many immune-related diseases also follow a circadian pattern and REV-ERB is now well established as a regulator of inflammation.29 Repression of Tlr4 in macrophages by REV-ERB decreases IL-6 production, blocking the inflammatory response. REV-ERB degradation under inflammatory conditions results in Tlr4 gene expression and successful inflammatory response, but, in turn, drives downregulation of many other circadian processes.30,31 Also in the field of immune regulation, TH17 cells have been 32–34 established as REV-ERB regulated effectors. TH17 are proinflammatory immune cells that produce Interleukin 17 (IL17) cytokines and play an important role in host defence against infection. However, the long half-life and strong cytokine secretion 33 of TH17 cells are often related to autoimmune complications. REV-ERB has been reported to negatively regulate TH17 development by competing with RORγt for the RORE region of key TH17 genes, reducing IL17 and other associated 33,34 proinflammatory cytokines such as IL6 or IFNγ. In this scenario, the use of REV-ERB activatory agonist ligands could be Figure2.

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