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Significance SR9009 has been described as an agonist for circadian nuclear receptors REV-ERBα and -β, and its pleotropic biological effects have been attributed to REV-ERBs in numerous publications, as well as websites selling the compound illicitly to the lay public. Here, a conditional REV-ERBα/β double-deletion mouse model was generated and used to test the specificity of SR9009 and a related compound. SR9009 was found to exert REV-ERB–independent effects on proliferation, metabolism, and gene transcription in 2 different cell types depleted of REV-ERBs. Therefore, effects of these drugs cannot be exclusively attributed to its actions on REV-ERBs, and it is imperative that investigators using the drug be made aware of this.

SR9009 has REV-ERB–independent effects on cell proliferation and metabolism