Emerging Microtubule Stabilizing Agents for Cancer Chemotherapy

David C. Myles Kosan Biosciences, Inc. 3832 Baycenter Place, Hayward, CA 94545

Introduction - The discovery of the potent anti-cancer properties and subsequent elucidation of the mechanism of action of paclitaxel firmly established this compound as a leader in the treatment of difficult cancers. In addition, the unusual mechanism of action of paclitaxel, the stabilization of microtubules, distinguished it from other microtubule-binding agents, such as the vinca alkaloids, that act by destabilizing microtubules. In this paper, recent advances in the identification of non-taxane microtubule stabilizing agents for cancer chemotherapy will be discussed with an emphasis on work published in 2000-02.

Microtubule (MT) stabilizing agents target the dimer of a- and p-tubulin, binding in a hydrophobic cleft on the p form, and promote the formation of and impart unusual stability to the microtubule (1). The chemistry and structural biology of this interaction and the interaction of other families of drugs that bind to microtubules has been the object of considerable study using a range of techniques, particularly photo affinity labeling (2). Not surprisingly, these experiments show that the site targeted by MT stabilizing drugs is distinct and well separated from the site at which other mechanistic classes of MT interacting agents bind to the target. More recently, an electron diffraction structure of oligomeric a,p-tubulin prepared in the presence of paclitaxel confirmed the presence of the drug in the site suggested by the earlier labeling experiments (3). The low resolution (ca. 4 A) of the structure makes structure-based drug design based on it difficult.

During mitosis, the interaction of drugs with the microtubule interferes with the proper formation of the mitotic spindle and causes arrest of the cell cycle at the G2/M transition. This effect ultimately results in apoptosis. The MT stabilizing effect of paclitaxel and other MT stabilizing agents can also be observed in vitro using mammalian a- and p-tubulin. Thus, data from in vitro cytotoxicity, microtubule bundling, and flow cytometry can all be used to drive medicinal chemistry efforts directed toward identifying novel potent analogs of existing microtubule stabilizing agents.

ANNUAL REPORTS IN MEDICINAL CHEMISTRY—37

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