Imatinibchemotherapeutical agent used in chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs) and a number of other malignancies. It is occasionally referred to as CGP57148B or STI571 (especially in older publications). It is being marketed by the pharmaceutical company Novartis as Gleevec® (USA) or Glivec® (Europe).
Imatinib is a 2-phenylaminopyridine derivative that functions as a specific inhibitor of a number of tyrosine kinase enzymes. It occupies the TK domain, leading to a decrease in activity.
There is a large number of TK enzymes in the body, including the insulin receptor. Imatinib is specific for the TK domain in abl (the Abelson proto-oncogene), c-kit and PDGF-R (platelet-derived growth factor receptor).
In chronic myelogenous leukemia, the Philadelphia chromosome leads to a fusion protein of abl with bcr (breakpoint cluster region), termed bcr-abl. As this is now a continuously active tyrosine kinase, Imatinib is used to decrease bcr-abl activity.
Although the late side effects of Gleevec have not yet been ascertained due to the newness of the drug, it seems to be generally very well tolerated (eg. liver toxicity was much less than predicted). Broadly, side effects such as oedema, nausea, rash and musculoskeletal pain are common but mild. Gleevec has passed through Phase III trials for CML, and has been shown to be more effective than the then standard treatment of interferon-alpha and cytarabine. As a result of this in America the Food and Drug Administration (FDA) has approved it as first-line treatment for CML (Deininger and Druker, 2003).
Imatinib was identified in the late 1990's by Dr Brian J. Druker for the pharmaceutical company Novartis as a potential agent for the use in CML.Its development is the template for rational drug design. Following the identification of the BCR-ABL target began the search for an inhibitor. Chemists used a high-throughput screen of chemical libraries to identify the molecule 2-phenylaminopyrimidine. This lead compound was then tested and modified by the introduction of methyl and benzamide groups to give it enhanced binding properties, resulting in imatinib (Druker and Lydon, 2000).