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.
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.
Xu
Jun
J
Oncology and Chemical and Screening Sciences, Wyeth Research, 401 North Middletown Road, Pearl River, New York 10965, USA.
Cole
Derek C
DC
Chang
Chao-Pei Betty
CP
Ayyad
Ramzi
R
Asselin
Magda
M
Hao
Wenshan
W
Gibbons
James
J
Jelinsky
Scott A
SA
Saraf
Kathryn A
KA
Park
Kaapjoo
K
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*
D004952:Esters; D015363:Quinolones; D050796:STAT3 Transcription Factor