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  • Title: GSK4112, a small molecule chemical probe for the cell biology of the nuclear heme receptor Rev-erbα.
    Author: Grant D, Yin L, Collins JL, Parks DJ, Orband-Miller LA, Wisely GB, Joshi S, Lazar MA, Willson TM, Zuercher WJ.
    Journal: ACS Chem Biol; 2010 Oct 15; 5(10):925-32. PubMed ID: 20677822.
    Abstract:
    The identification of nonporphyrin ligands for the orphan nuclear receptor Rev-erbα will enable studies of its role as a heme sensor and regulator of metabolic and circadian signaling. We describe the development of a biochemical assay measuring the interaction between Rev-erbα and a peptide from the nuclear receptor corepressor-1 (NCoR). The assay was utilized to identify a small molecule ligand for Rev-erbα, GSK4112 (1), that was competitive with heme. In cells, 1 profiled as a Rev-erbα agonist in cells to inhibit expression of the circadian target gene bmal1. In addition, 1 repressed the expression of gluconeogenic genes in liver cells and reduced glucose output in primary hepatocytes. Therefore, 1 is useful as a chemical tool to probe the function of Rev-erbα in transcriptional repression, regulation of circadian biology, and metabolic pathways. Additionally, 1 may serve as a starting point for design of Rev-erbα chemical probes with in vivo pharmacological activity.
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