Strategies for the development of novel Taxol-like agents.

Taxol, the first microtubule stabilizer identified, is one of the most important new anticancer drugs to be brought to the clinic in the past 20 yr. The clinical success of TaxolTM led to the development of a second-generation taxane, docetaxel (Taxotere), and multiple third-generation taxane derivatives are under development. Non-taxane microtubule-stabilizers of diverse chemical structures, including the epothilones and discodermolide, show promising preclinical activities and several epothilones are progressing through clinical trials. One important advantage of the new stabilizers is their ability to circumvent drug resistance mechanisms. The clinical development of these new classes of agents suggests that microtubule stabilizers will continue to be important drugs for the treatment of cancer. This chapter provides a brief history of Taxol and the discovery and development status of other classes of microtubule stabilizers. Although all microtubule-stabilizers share similar mechanisms of action, interesting subtle differences among the stabilizers are being detected. This chapter also provides some strategies for identifying the differences among microtubule stabilizers that may help prioritize them for development and clinical use.