Imatinib

Helping orphans the way you would do it

Imatinib (usually as mesylate) is a novel chemotherapeutical 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).

Molecular biology

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.

Imatinib works because p210BCR-ABL requires a molecule of ATP to phosphorylate tyrosine residues on its substrates, and hence activate them. Gleevec instead docks in to this site and inhibits the protein competitively. Imatinib is quite selective for BCR-ABL ÃÂÃÂ it does also inhibit other targets mentioned above, but no known other tyrosine kinases. Imatinib does of course work on the ABL protein of all cells but these have additional, normally redundant, pathways which allow the cell to continue to function normally even without this one. Tumour cells, however, have a dependence on BCR-ABL (Deininger and Druker, 2003). Inhibition of the BCR-ABL tyrosine kinase also stimulates its entry in to the nucleus, where it is unable to perform any of its normal anti-apoptopic functions (Vigneri et al., 2001).

Uses

Imatinib is used in chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs) and a number of other malignancies. Please refer to the relevant articles for more information.

Tolerance

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).

History

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).

References

Deininger M and Druker BJ. (2003). Specific Targeted Therapy of Chronic Myelogenous Leukemia with Imatinib. Pharmacol Rev, 55:401-423

Druker BJ, Lydon NB. (2000). Lessons learned from the development of an Abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J Clin Invest 2000;105:3-7. PMID 10619854
Vigneri P and Wang JY. (2001). Induction of apoptosis in chronic myelogenous leukemia cells through nuclear entrapment of BCR-ABL tyrosine kinase. Nat Med, 7:228-234