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In melanoma cell lines, \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    AR activation leads to the suppression of pro-proliferatory MAPK\/ERK signaling. This suggests that fenoterol, a potent \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    AR agonist, can be useful in the treatment of melanoma. Here, we investigated the structure\u2013activity relationship (SAR) of fenoterol derivatives for \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    AR-depedent ERK suppression.\u00a0We 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.\u00a0(\n                    <jats:italic>R<\/jats:italic>\n                    ,\n                    <jats:italic>R<\/jats:italic>\n                    \u2032) stereoisomers of fenoterol derivatives exhibited the highest suppression of ERK phosphorylation, followed by (\n                    <jats:italic>R<\/jats:italic>\n                    ,\n                    <jats:italic>S<\/jats:italic>\n                    \u2032) and (\n                    <jats:italic>S<\/jats:italic>\n                    ,\n                    <jats:italic>R<\/jats:italic>\n                    \u2032) isomers, with (\n                    <jats:italic>S<\/jats:italic>\n                    ,\n                    <jats:italic>S<\/jats:italic>\n                    \u2032) isomers being the least active, mirroring trends observed in \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    AR binding and cAMP accumulation. SAR analysis revealed that modifications to the \u03b1\u2032 alkyl chain and the 4\u2032-hydroxy moieties significantly affected ERK-inhibitory activity of fenoterol derivatives. (\n                    <jats:italic>R<\/jats:italic>\n                    ,\n                    <jats:italic>R<\/jats:italic>\n                    \u2032)-4\u2032-hydroxy-1-naphthylfenoterol [(\n                    <jats:italic>R<\/jats:italic>\n                    ,\n                    <jats:italic>R<\/jats:italic>\n                    \u2032)-HNF] was the most active inhibitor of ERK activation with an IC\n                    <jats:sub>50<\/jats:sub>\n                    of 0.03\u00a0nM. However, it showed minimal anti-proliferative activity in the zebrafish xenograft model. In contrast, (\n                    <jats:italic>R<\/jats:italic>\n                    ,\n                    <jats:italic>R<\/jats:italic>\n                    \u2032)-4\u2032-methoxy-1-naphthylfenoterol [(\n                    <jats:italic>R<\/jats:italic>\n                    ,\n                    <jats:italic>R<\/jats:italic>\n                    \u2032)-MNF], a weaker ERK inhibitor (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20090.17\u00a0nM), significantly reduced cell viability in vitro (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u200914.07\u00a0\u00b5M) and tumor growth in vivo.\u00a0SAR for fenoterol-mediated ERK inhibition in melanoma was defined, highlighting the importance of the (\n                    <jats:italic>R<\/jats:italic>\n                    ,\n                    <jats:italic>R<\/jats:italic>\n                    \u2032) stereochemistry. Crucially, potent ERK inhibition does not directly predict anti-tumorigenic activity, as shown by (\n                    <jats:italic>R<\/jats:italic>\n                    ,\n                    <jats:italic>R<\/jats:italic>\n                    \u2032)-HNF. The pronounced anti-proliferatory effect of (\n                    <jats:italic>R<\/jats:italic>\n                    ,\n                    <jats:italic>R<\/jats:italic>\n                    \u2032)-MNF, despite weaker ERK inhibition, implies additional mechanisms beyond ERK modulation.\n                  <\/jats:p>","DOI":"10.1007\/s00210-026-05564-7","type":"journal-article","created":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T03:14:00Z","timestamp":1781925240000},"page":"19201-19213","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel fenoterol derivatives as suppressors of ERK1\/2 phosphorylation in melanoma"],"prefix":"10.1007","volume":"399","author":[{"given":"Jakub","family":"W\u00f3jcik","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylwia","family":"Wnorowska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weronika","family":"Miziewicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Tassinari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela","family":"Misiurek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Kostecki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agata","family":"Ma\u0142ek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Boguszewska-Czubara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irving W.","family":"Wainer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Artur","family":"Wnorowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,20]]},"reference":[{"key":"5564_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.102636","volume":"298","author":"JD Chrispell","year":"2022","unstructured":"Chrispell JD, Xiong Y, Weiss ER (2022) Grk7 but not Grk1 undergoes cAMP-dependent phosphorylation in zebrafish cone photoreceptors and mediates cone photoresponse recovery to elevated cAMP. 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Dr. Wainer has assigned his rights in the patents to the U.S. government, but will receive a percentage of any royalties that may be received by the government. Dr. Wainer is currently Chief Scientific Officer at PAZ Pharma, which has an exclusive license for the use of MNF and related compounds in the treatment of pancreatic, liver, and brain cancers. The remaining authors state no conflict of interest.","order":1,"name":"Ethics","label":"Competing Interests","group":{"name":"EthicsHeading","label":"Declarations"}}]}}