SR9011 hydrochloride is a REV-ERBα/β agonist, exhibiting IC50 values of 790 nM for REV-ERBα and 560 nM for REV-ERBβ.

Rev-ErbBα:790 nM (IC50), Rev-ErbBβ:560 nM (IC50)

SR9011 enhances REV-ERB's repressive activity in a dose-dependent manner, as demonstrated in HEK293 cells equipped with both a chimeric Gal4 DNA Binding Domain (DBD)-REV-ERB ligand binding domain (LBD) α or β and a Gal4-responsive luciferase reporter, with IC50 values of 790 nM for REV-ERBα and 560 nM for REV-ERBβ. Additionally, SR9011 effectively inhibits transcription through a cotransfection assay using full-length REV-ERBα and a luciferase reporter under the control of the Bmal1 promoter (IC50 = 620 nM). This compound also downregulates BMAL1 mRNA expression in HepG2 cells via REV-ERBα/β. Notably, SR9011 inhibits the proliferation of breast cancer cell lines, irrespective of their ER or HER2 status, by inducing cell cycle arrest before the M phase, possibly through direct suppression of Cyclin A (CCNA2) expression, a known target of REV-ERB. This action leads to an accumulation of cells in the G0/G1 phase and a concurrent reduction in the S and G2/M phases, hinting at REV-ERB activation's role in impeding progression from G1 to S phase and/or from S to G2/M phase.

SR9011 demonstrates adequate plasma exposure, influencing the expression of genes responsive to REV-ERB in mice liver after different dosages for 6 days. The gene for plasminogen activator inhibitor type 1 (Serpine1), targeted by REV-ERB, shows a dose-dependent decrease in expression following SR9011 treatment. Similarly, the cholesterol 7α-hydroxylase (Cyp7a1) and sterol response element binding protein (Srepf1) genes, both responsive to REV-ERB, exhibit dose-dependent suppression with increased SR9011 dosages. After 12 days under constant darkness, a single SR9011 injection at CT6 disrupts circadian-related locomotor activity, with normal activity resuming after a cycle, indicative of the drug's clearance within 24 hours. This effect, as well as the dose-dependent decrease in wheel running behavior under constant darkness, suggests SR9011's potency (ED50 = 56 mg/kg) is comparable to its efficacy in suppressing the Srebf1 gene in vivo (ED50 = 67mg/kg).