Imatinib and its use in CML

Targeting tyrosine kinases in cancer therapies

The Bcr-Abl oncoprotein is an example of a tyrosine kinase run amok with its kinase activity - it phosphorylates several proteins eventually leading to a Chronic Myelogynous leukemia (CML) phenotype. Scientists understood that CML transformation of cells by Bcr-Abl was inextricably tied to the tyrosine kinase activity, which suggested that targeting the kinase activity of the oncoprotein would be be therapeutically meaningful. Seeing that healthy people do not have the Philadelphia chromosome (producing Bcr-Abl), an inhibitor against Bcr-Abl would selectively target cancer cells only in individuals harboring the Philadelphia chromosome. With this rationale in mind, imatinib was developed as a semi-competitive inhibitor of Bcr-Abl kinase domain (the part of the protein responsible for phosphorylation). In 2001, imatinib was approved for use in humans and was immediately hailed as an "essential medicine" because it has:

• low toxicity - relatively safe for use in humans compared to other chemotherapy drugs that may present with serious side effects.
• high bioavailability - the drug is available in high concentration to cells which then metabolize the drug very effectively.
• specificity - most anti-cancer drugs inhibit cell proliferation in a non-specific manner - they prevent several different types of cells from dividing. Imatinib is different in that targets cancer cells only.

In the USA, imatinib is marketed by Novartis as "Gleevec" and as "Glivec" in Europe and Australia. The mesylate salt of imatinib is used commonly used as a first-line treatment of CML and is the first generation tyrosine kinase inhibitor.

How does imatinib inhibit Bcr-Abl?

The 'inib' in imatinib indicates that this drug is a tyrosine kinase inhibitor. In CML, the fusion of Bcr to Abl results in the formation of Bcr-Abl oncoprotein with hyperactive tyrosine kinase activity. Like all kinases, Bcr-Abl requires ATP (which is the energy currency inside the cell rich in phosphate groups) to "transfer" a phosphate group to a tyrosine amino acid residue on a target protein. A good analogy is one using blocks: Imatinib (blue block) works by competing with target proteins (green block) to bind to the catalytic domain of Bcr-Abl (red block). By binding to Bcr-Abl, imatinib essentially stabilizes the kinase, thereby inhibiting its tyrosine kinase activity. Think of the red and blue blocks glued together preventing the green block to attach - in this way imatinib prevents phosphorylation of tyrosines on other proteins. Because phosphorylation of target proteins is required for turning on signaling pathways that lead to CML disease, imatinib's inhibition of Bcr-Abl results in the overall dampening of the phosphorylation cascade leading to reduction in proliferation of CML cells. Patients with CML who respond to imatinib treatment and remain in remission after two years tend to have the same life expectancy as healthy individuals - a remarkable achievement in the fight against cancer! Current medical advancements cannot reverse the formation of Philadelphia chromosome, so people with CML have to take imatinib indefinitely to stay healthy.

As often happens in nature, cells can develop resistance against imatinib by way of mutations. Most commonly this happens, when mutations in Bcr-Abl allow the oncoprotein to "remove" imatinib and continue with aberrant kinase activity. In such an event, physicians may prescribe the use of second or third generation tyrosine kinase inhibitors that will continue to be effective against Bcr-Abl oncoprotein.