The background, discovery and clinical development of BCR-ABL inhibitors

• Background to kinases and their role in disease, particularly cancer.
• The discovery and development of kinase inhibitors for clinical use.
• Understanding mode(s) of action to overcome resistance.
• Impact of structure-based drug design in developing new generations of compound.
• A timely review providing a valuable background resource.

The story of the inhibition of BCR-ABL as a treatment for chronic myelogenous leukaemia serves to illustrate key aspects of the kinase drug discovery and development process. Firstly, elucidation of the disease mechanism enabled identification of the molecular target(s) which catalysed pharmaceutical research and resulted in Gleevec® (Novartis) as the first FDA approved BCR-ABL inhibitor. However, clinical success was soon tempered by the emergence of drug resistance through various mechanisms. Using rational drug design, several hypotheses were devised to overcome resistance issues leading to the development of second generation inhibitors, providing clinicians and patients with greater therapeutic choice.