GSK4112, a Small Molecule Chemical Probe for the Cell Biology of the Nuclear Heme Receptor Rev-erbα

被引：114

作者：

Grant, Daniel ^{[4
]}

Yin, Lei ^{[1
,2
,3
]}

Collins, Jon L. ^{[4
]}

Parks, Derek J. ^{[4
]}

Orband-Miller, Lisa A. ^{[4
]}

Wisely, G. Bruce ^{[4
]}

Joshi, Shree ^{[1
,2
,3
]}

Lazar, Mitchell A. ^{[1
,2
,3
]}

Willson, Timothy M. ^{[4
]}

Zuercher, William J. ^{[4
]}

机构：

[1] Univ Penn, Sch Med, Div Endocrinol Diabet & Metab, Dept Med, Philadelphia, PA 19104 USA

[2] Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA

[3] Univ Penn, Sch Med, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA

[4] GlaxoSmithKline Inc, Res Triangle Pk, NC 27707 USA

来源：

ACS CHEMICAL BIOLOGY | 2010年 / 5卷 / 10期

关键词：

CIRCADIAN TRANSCRIPTION; COACTIVATOR PGC-1; IDENTIFICATION; LIGAND; CLOCK; BETA; E75; MECHANISMS; GENE;

D O I：

10.1021/cb100141y

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The identification of nonporphyrin ligands for the orphan nuclear receptor Rev-erb alpha 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-erba and a peptide from the nuclear receptor corepressor-1 (NCoR). The assay was utilized to identify a small molecule ligand for Rev-erba, GSK4112 (1), that was competitive with heme. In cells, 1 profiled as a Rev-erb alpha agonist in cells to inhibit expression of the circadian tar, get 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-erb alpha in transcriptional repression, regulation of circadian biology, and metabolic pathways. Additionally, 1 may serve as a starting point for design of Rev-erba chemical probes with In vivo pharmacological activity.

引用

页码：925 / 932

页数：8

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