REV-ERB is a member of the nuclear receptor (NR) superfamily of intracellular transcription factors. Besides, REV-ERB also is a key regulatory component of the circadian clock. Meanwhile, REV-ERB regulates the rhythmic expression of inflammatory, metabolic, and cellular proliferative genes. Importantly, REV-ERB is a particularly efficacious transcriptional repressor, and they lack the carboxy-terminal activation function 2 domain required for coactivator protein recruitment. Moreover, studies show that REV-ERB agonists may be useful in treating diseases associated with inflammation, metabolic dysfunction, and cancer.

STL1267, a potent and cross-the-blood-brain barrier REV-ERB agonist.

STL1267 displays a particularly strong level of recruitment of the corepressor NCoR with an EC₅₀ value of 0.13 µM. Mainly, STL1267 binds directly to the ligand binding domain (LBD) with a K_i value of 0.16 µM for REV-ERBα. Besides, STL1267 is an activator of transcription effectively enhancing the sensitivity with an EC₅₀ value of 1.8 µM in HEK293 cells.

This compound (0-20 µM; 24 h) shows no adverse effects on cell viability up to the maximum dose examined 20 µM for HepG2, C2C12 cells. Moreover, STL1267 (5 µM; 24 h) decreases the gene expression of BMAL1, increases the gene expression of Mtnd1, Mtco1, Vicad, Lcad, Scad, Lkb1, Sirt1, Nampt, Ppargc1a in HepG2 cells. In vivo, STL1267 (50 mg/kg; intraperitoneal injection; once) shows plasma half-life of STL1267 was ~1.6 h in C57Bl/6 J mice. In addition, STL1267 successfully crosses the blood-brain barrier with brain levels similar to plasma levels. Moreover, It effectively suppresses BMAL1 expression in the liver at 12 h post.

All in all, STL1267 is a potent and cross-the-blood-brain barrier REV-ERB agonist. Besides, STL1267 suppresses BMAL1 expression in mice.

Reference:

[1]  Murray MH, et al. Nat Commun. 2022 Nov 21;13(1):7131.