New England Journal - Editorial

Sawyers, M.D

The clinical success of imatinib in patients with chronic myeloid leukemia (CML), which was first reported 9 years ago,1 catalyzed a systemwide shift in the development of cancer drugs to include molecularly targeted therapies. According to one recent estimate, approximately 200 such drugs are now in the clinical-development pipeline. First approved for interferon-resistant CML, imatinib quickly became the standard of care in patients with newly diagnosed CML on the basis of the drug's remarkable efficacy (complete cytogenetic remissions in some 70% of patients) with minimal toxic effects when used as initial therapy.2 Success of that magnitude is rare in oncology.

But imatinib was the first drug of its kind — an early foray into the world of kinase inhibition when the properties of the ideal candidate drug were completely unknown. By today's standards, imatinib has relatively low potency and inhibits its target at micromolar rather than nanomolar concentrations. In addition, imatinib is susceptible to resistance through a large number of different mutations in the BCR-ABL target as a consequence of the way it binds the BCR-ABL kinase domain, an unforeseen issue at the time of its discovery.

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