4-Anilino-3-quinolinecarbonitriles: An Emerging Class of Kinase Inhibitors - An Update

Author(s): Diane H. Boschelli

Journal Name: Medicinal Chemistry Reviews - Online (Discontinued)

Volume 1 , Issue 4 , 2004


In 2000, Wyeth disclosed that 4-(3-bromoanilino)-6,7-dimethoxy-3-quinolinecarbonitrile was a potent and selective EGFR kinase inhibitor. Subsequent reports showed that variation of the substituents on the 4-anilino group of the 3-quinolinecarbonitrile core changed the kinase specificity from EGFR to either Src or MEK. This article is an update of a 2002 review that summarized Wyeths efforts in the area of 4-anilino-3-quinolinecarbonitrile kinase inhibitors. Since then, Wyeth has reported the SAR of EKB-569, an irreversible EGFR inhibitor currently in clinical trials. Variation of the 4-anilino group of EKB-569 provided HKI-272, a dual inhibitor of EGFR and HER-2. In addition, the 3- quinolinecarbonitrile analogs of known quinazoline EGFR inhibitors were prepared. SKI-606, initially reported to be a Src inhibitor, was found to also inhibit Abl kinase and therefore could be a potential alternative treatment to Gleevec. SKI-606 was also efficacious in a rat model of stroke. Additional Src kinase inhibitors, including some tricyclic analogs, were obtained by variation of the substituent at C-7. Finally, 3-quinolinecarbonitrile MEK inhibitors with potent cell activity were identified.

Keywords: 4-Anilino-3-quinolinecarbonitriles, quinazoline, EGFR inhibitors, HER-2, SKI-606

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Article Details

Year: 2004
Page: [457 - 463]
Pages: 7
DOI: 10.2174/1567203043401545
Price: $58

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