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

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 Wyeth's 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.