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.