Butyl 4-(butyryloxy)benzoate functions as a new selective estrogen receptor beta agonist and induces GLUT4 expression...

Estrogen receptors (ERs) belong to nuclear hormone receptor superfamily and can be activated by estrogens and regulate many target genes. Two ER isoforms, ERalpha and ERbeta have been discovered to date and ERbeta was indicated to involve in anti-inflammatory and anti-diabetogenic effects. Recently, some studies also demonstrated an association between ERbeta and GLUT4 expression. The development of selective ERbeta ligand has facilitated probing its novel biological functions and clinical benefits. In this work, a new ERbeta selective agonist, butyl 4-(butyryloxy)benzoate (DCW234), was discovered as investigated by surface plasmon resonance (SPR) technology, yeast two-hybrid and cell-based transcription-based assays. SPR results demonstrated that DCW234 has a higher binding affinity against ERbeta over ERalpha and induces a strong and selective stimulation on ERbeta/SRC1 interaction, which could be efficiently blocked by Tamoxifen. Meanwhile, the yeast two-hybrid technology-based assay indicated that DCW234 exhibits a higher agonistic activity ( approximately 13-fold) in stimulating ERbeta ligand-binding domain (LBD) interaction with SRC1 (EC(50)=2.5 microM) than ERalpha-LBD/SRC1 interaction (EC(50)=32.7 microM). The cell-based transcriptional assay further proved the potency and selectivity of DCW234. Moreover, DCW234 was found to be able to induce GLUT4 expression in CHO-K1 cell. The discovered DCW234 might be hopefully developed as a potential lead compound for further research.