4-anilino-3-quinolinecarbonitriles: an emerging class of kinase inhibitors.
The first potent selective small molecule inhibitor of a protein kinase was reported in 1994 by Parke-Davis. PD-153035, 4-(3-bromoanilino)-6,7-dimethoxyquinazoline, is an ATP competitive inhibitor of the epidermal growth factor receptor tyrosine kinase (EGFr), with no appreciable inhibitory activity against several other kinases. Subsequent structural elaboration of PD-153035 led to several 4-anilinoquinazolines that are currently in various stages of clinical trials for the treatment of kinase-mediated diseases. A homology model of EGFr with PD-153035 suggested that the 3-nitrogen atom of the quinazoline ring binds a water molecule. It was envisioned that this nitrogen atom could be replaced by a carbon atom containing an electron-withdrawing group. This critical observation by a group at Wyeth led to the identification of 4-(3-bromoanilino)-6,7-dimethoxy-3-quinolinecarbonitrile as an EGFr inhibitor. It was subsequently established that variation of the substituents on the 4-anilino group of the 6,7-dimethoxy-3-quinolinecarbonitrile changed the kinase specificity from EGFr to other kinases including Src and MEK. The 3-quinolinecarbonitrile template was also utilized to develop an irreversible inhibitor of EGFr, EKB-569, currently in clinical trials for the treatment of cancer. Further manipulation of the 3-quinolinecarbonitrile core provided tricyclic analogs, with the most potent kinase inhibitory activity observed with a benzo[g]quinoline-3-carbonitrile ring system. It was also found that 3-quinolinecarbonitriles with a 7-thiophene or phenyl substituent were potent Src kinase inhibitors.
Boschelli
Diane H
DH
Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10956, USA. bosched@wyeth.com
D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
D000814:Aniline Compounds; D004791:Enzyme Inhibitors; D009570:Nitriles; D011799:Quinazolines; D066246:ErbB Receptors; D019061:src-Family Kinases; D017346:Protein Serine-Threonine Kinases; C088860:4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline