Ixabepilone (Ixempra; Bristol-Myers Squibb), a cytotoxic microtubule inhibitor, was approved by the US FDA for the treatment of metastatic breast cancer in October 2007. It is the first member of the epothilone family of anticancer agents to be approved.
Microtubule-targeted drugs — in particular, the taxanes paclitaxel and docetaxel — have had a major impact on the treatment of many cancers including breast cancer, the most common cancer affecting women worldwide. Nevertheless, there are a number of areas in which microtubule-targeted therapy could be improved, including increased activity against cancers that are less responsive to taxanes or against cancers in which taxane resistance has developed following treatment
Basis of discovery
Microtubules — polymeric filaments composed of alpha-tubulin and beta-tubulin heterodimers — have a key role in a range of cellular functions, including cell division and growth For example, microtubules are a major component of the mitotic spindle that separates chromosomes during eukaryotic cell division
Microtubules show complex polymerization dynamics that are crucial to their cellular functions. Several families of compounds that interact with the tubulin subunits and thereby disrupt microtubule dynamics involved in mitosis have been found to have potent anticancer activity . These anti-mitotic compounds are typically classified into two main groups: microtubule-destabilizing agents, such as the Vinca alkaloids, and microtubule-stabilizing agents, such as the taxanes . The clinical success of the taxanes has encouraged efforts to identify and develop other classes of microtubule-targeted anticancer compounds that might overcome the limitations of existing drugs.
The epothilones, which are produced by the myxobacterium Sorangium cellulosum, are a novel class of microtubule-stabilizing agents that were discovered in the early 1990s . Epothilones A and B were found to have potent in vitro anticancer activity, including activity against taxane-resistant cell lines, but their in vivo activity is modest, owing to issues such as poor metabolic stability and unfavourable pharmacokinetics . Synthesis and testing of more than 300 semisynthetic epothilone analogues with the aim of addressing these issues led to the identification of ixabepilone .