GSK 4112

IC50: 2.3 μM

GSK4112 is a synthetic antagonist of the Nuclear Heme Receptor REV-ERB.

Rev-erbα and Rev-erbβ are heme sensors and atypical members of the nuclear receptor superfamily. As a member of the nuclear receptor superfamily, REV-ERBR functions as a receptor for the porphoryin heme. REV-ERBR can suppress the transcription of its target genes in a heme-dependent manner.

In vitro: Previous study showed that GSK4112 addition to either the REV-ERBR or REV-ERBβ assay led to enhanced repression. Cells were treated the with GSK4112 and similar pattern in GAL4 chimeric receptor assay was observed. In addition, GSK4112 suppressed reporter gene expression. GSK4112 also suppressed transcription driven by the Bmal1 promoter dose-dependently. GSK4112 activity was found to be associated with REV-ERBR [1].

In vivo: GSK4112 was found to display poor pharmacokinetic properties (rat liver microsomal Cint > 1.0 mL/min/mg protein; lack of oral bioavailability (F < 1% in mice)), which likely limited its use to biochemical and cell-based assays. As a result, GSK4112 was unlikely to be suitable for in vivo studies [1].

Clinical trial: N/A

Reference:
[1] Daniel Grant,Lei Yin,Jon L.  Collins et al. GSK4112, a small molecule chemical probe for the cell biology of the nuclear Heme receptor Rev-erbα. ACS CHEMICAL BIOLOGY5(10):925-32.

The nuclear receptor and clock gene REV-ERBalpha regulates cigarette smoke-induced lung inflammation.[Pubmed:28974420]

Biochem Biophys Res Commun. 2017 Dec 2;493(4):1390-1395.

REV-ERBalpha is a nuclear heme receptor, transcriptional repressor and critical component of the molecular clock that drives daily rhythms of metabolism. Evidence reveals that REV-ERBalpha also plays an important regulatory role in clock-dependent lung physiology and inflammatory responses. We hypothesize that cigarette smoke (CS) exposure influences REV-ERBalpha abundance in the lungs, facilitating a pro-inflammatory phenotype. To determine the impact of REV-ERBalpha activation in the CS-induced inflammatory response we treated primary human small airway epithelial cells (SAECs) with CS extract (CSE) or lipopolysaccharide (LPS) in the absence or presence of pre-treatment with the REV-ERBalpha agonist GSK 4112. We also exposed adult C57BL/6J (WT) and Rev-erbalpha global KO mice to CS (10 and 30 days) and measured pro-inflammatory cytokine release. Our data reveal that pre-treatment with GSK 4112 reduced CSE/LPS induced pro-inflammatory cytokines release from both SAECs and mouse lung fibroblasts (MLFs). Furthermore, REV-ERBalpha KO mice show a greater inflammatory response to 10 and 30 days of CS, including increased neutrophil lung influx, pro-inflammatory cytokine (IL-6, MCP-1 and KC) release, and pro-senescence marker (p16) when compared to WT mice. These data demonstrate that REV-ERBalpha is a critical regulator of CS-induced lung inflammatory responses.

Identification of SR8278, a synthetic antagonist of the nuclear heme receptor REV-ERB.[Pubmed:21043485]

ACS Chem Biol. 2011 Feb 18;6(2):131-4.

REV-ERBalpha is a member of the nuclear receptor superfamily that functions as a receptor for the porphoryin heme. REV-ERBalpha suppresses transcription of its target genes in a heme-dependent manner. Recently, the first nonporphyrin synthetic ligand for REV-ERBalpha, GSK4112, was designed, and it mimics the action of heme acting as agonist. Here, we report the identification of the first REV-ERB antagonist, SR8278. SR8278 is structurally similar to the agonist but blocks the ability of the GSK4112 to enhance REV-ERBalpha-dependent repression in a cotransfection assay. Additionally, whereas GSK4112 suppresses the expression of REV-ERBalpha target genes involved in gluconeogenesis, SR8278 stimulates the expression of these genes. Thus, SR8278 represents a unique chemical tool for probing REV-ERB function and may serve as a point for initiation of further optimization to develop REV-ERB antagonists with the ability to explore circadian and metabolic functions.

GSK4112 is a Rev-erbα agonist with EC50 of 0.4 μM, also is a small molecule chemical probe for the cell biology of the nuclear heme receptor Rev-erbα.

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