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

  • J Med Chem. 2008 Jul 24;51(14):4115-21. doi: 10.1021/jm701271y.
Jun Xu  1 ,  Derek C Cole ,  Chao-Pei Betty Chang ,  Ramzi Ayyad ,  Magda Asselin ,  Wenshan Hao ,  James Gibbons ,  Scott A Jelinsky ,  Kathryn A Saraf ,  Kaapjoo Park
Affiliations
  • 1. Oncology and Chemical and Screening Sciences, Wyeth Research, 401 North Middletown Road, Pearl River, New York 10965, USA.
PMID: 18578470 DOI: 10.1021/jm701271y
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.

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