title: Inhibition of the signal transducer and activator of transcription-3 (STAT3) signaling pathway by 4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxylic acid esters.
abstract: The JAK-STAT3 pathway regulates genes that are important in cell proliferation and thus is a promising target for cancer therapy. A high-throughput screening (HTS) campaign using an Apo-ONE Homogenous Caspase 3/7 assay in U266 cells identified 4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxylic acid ethyl ester 4 as a potential STAT3 pathway inhibitor. Optimization of this HTS hit led to the identification of the 7-cyano analogue 8, which inhibited STAT3-Y705 phosphorylation with an EC 50 of 170 nM. Compound 8 also inhibited cytokine induced JAK activation but did not inhibit BCR-ABL activated STAT5 phosphorylation in K562 cells.
authors.affiliation: Oncology and Chemical and Screening Sciences, Wyeth Research, 401 North Middletown Road, Pearl River, New York 10965, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.forename: Derek C
authors.initials: DC
authors.lastname: Cole
authors.forename: Chao-Pei Betty
authors.initials: CP
authors.lastname: Chang
authors.forename: Ramzi
authors.initials: R
authors.lastname: Ayyad
authors.forename: Magda
authors.initials: M
authors.lastname: Asselin
authors.forename: Wenshan
authors.initials: W
authors.lastname: Hao
authors.forename: James
authors.initials: J
authors.lastname: Gibbons
authors.forename: Scott A
authors.initials: SA
authors.lastname: Jelinsky
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Saraf
authors.forename: Kaapjoo
authors.initials: K
authors.lastname: Park
mesh_terms: D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D004952:Esters; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D010766:Phosphorylation; D015363:Quinolones / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D004952:Esters; D015363:Quinolones; D050796:STAT3 Transcription Factor