Structural biology in the battle against BCR-Abl

Abstract

Background: The clinical success of the tyrosine kinase inhibitor imatinib (Gleevec; STI-571) in the treatment of several leukemias has emphasized the proof-of-concept that molecularly targeted drug design is a viable approach to cancer therapy. However, the emergence of imatinib-resistant phenotypes has spurred a vast amount of research towards finding newer and more potent kinase inhibitors that can overcome drug resistance. Unexpectedly, the newest inhibitors are often less specific than imatinib, inhibiting not only BCR-Abl (the target of imatinib), but also the Src family of tyrosine kinases, which have recently been shown to be downstream effectors of BCR-Abl. Objective: This review summarizes some of the new BCR-Abl inhibitors that have followed from the teaming of combinatorial library searches and structure-based drug design, giving attention to the structural aspects of drug recognition. Conclusion: The use of lower-specificity inhibitors seemingly undermines the rationale behind targeted therapy, yet it appears to be a critical aspect of overcoming drug resistance. Combination therapy with a cocktail of drugs, including an inhibitor of the T315I resistance mutation, will be the next maneuver in the battle against BCR-Abl in the treatment of chronic myelogenous leukemia.

Keywords::

• BCR-Abl
• c-Abl
• cancer
• CML
• kinase inhibitor
• kinases
• leukemia
• Src family

Acknowledgements

I thank Ahmad Kanaan for help in preparing some of the figures.