The development of HKI-272 and related compounds for the treatment of cancer.
The development of HKI-272 and EKB-569 for the treatment of cancer is described. These compounds function as irreversible inhibitors of some members of the ErbB family of receptor tyrosine kinases. In particular, they target epidermal growth factor receptor (EGFR, also known as ErbB-1) and human epidermal growth factor receptor-2 (HER2, also known as ErbB-2). Both, HKI-272 and EKB-569 are 4-anilino-3-cyano quinoline derivatives that contain a 4-(dimethylamino)crotonamide Michael-acceptor group at the 6-position. These compounds inhibit the function of the target enzymes by forming a covalent interaction with a conserved cysteine residue located in the kinase domains of these proteins. The potential advantages of using irreversible inhibitors for this purpose are discussed. We summarize the recent findings concerning some somatic mutations in EGFR and their relevance with respect to the irreversible inhibitors. In particular, we highlight the findings that these irreversible inhibitors retain activity against tumors that have acquired a resistance to the reversible binding inhibitors gefitinib and erlotinib. The promising interim clinical trial results for HKI-272 and EKB-569 in treating colon, lung, and breast cancers are summarized.
Wissner
Allan
A
Chemical and Screening Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, USA. wissnea@wyeth.com
Mansour
Tarek S
TS
D000634:Aminoquinolines / Q000138:chemical synthesis / Q000627:therapeutic use*; D000814:Aniline Compounds / Q000138:chemical synthesis / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D009369:Neoplasms / Q000188:drug therapy*; D011804:Quinolines / Q000138:chemical synthesis / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000634:Aminoquinolines; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D011804:Quinolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C487932:neratinib; C413879:EKB 569