Novel fenoterol derivatives as suppressors of ERK1/2 phosphorylation in melanoma
摘要
Melanoma is a highly aggressive cancer with limited therapeutic options. In melanoma cell lines, β2AR activation leads to the suppression of pro-proliferatory MAPK/ERK signaling. This suggests that fenoterol, a potent β2AR agonist, can be useful in the treatment of melanoma. Here, we investigated the structure–activity relationship (SAR) of fenoterol derivatives for β2AR-depedent ERK suppression. We used the UACC-647 human-derived melanoma cell line to screen a panel of chiral compounds based on the fenoterol scaffold. The levels of phosphoactive ERK1/2 were quantified by immunoblotting. Anti-tumorigenic activity of the drugs was assessed using MTS assay and zebrafish xenograft model. (R,R′) stereoisomers of fenoterol derivatives exhibited the highest suppression of ERK phosphorylation, followed by (R,S′) and (S,R′) isomers, with (S,S′) isomers being the least active, mirroring trends observed in β2AR binding and cAMP accumulation. SAR analysis revealed that modifications to the α′ alkyl chain and the 4′-hydroxy moieties significantly affected ERK-inhibitory activity of fenoterol derivatives. (R,R′)-4′-hydroxy-1-naphthylfenoterol [(R,R′)-HNF] was the most active inhibitor of ERK activation with an IC50 of 0.03 nM. However, it showed minimal anti-proliferative activity in the zebrafish xenograft model. In contrast, (R,R′)-4′-methoxy-1-naphthylfenoterol [(R,R′)-MNF], a weaker ERK inhibitor (IC50 = 0.17 nM), significantly reduced cell viability in vitro (IC50 = 14.07 µM) and tumor growth in vivo. SAR for fenoterol-mediated ERK inhibition in melanoma was defined, highlighting the importance of the (R,R′) stereochemistry. Crucially, potent ERK inhibition does not directly predict anti-tumorigenic activity, as shown by (R,R′)-HNF. The pronounced anti-proliferatory effect of (R,R′)-MNF, despite weaker ERK inhibition, implies additional mechanisms beyond ERK modulation.