Background

The development of the epothilones exemplifies rational scientific drug development. This class of cytotoxic products was first isolated by Gerhard Hofle and Hans Reichenbach in 1991 from the fermentation of the myxobacterium Sorangium cellulosum (1,2). The name of these agents is derived from their molecular features: epoxide, thiazole, and ketone (3). Bollag et al. (4) demonstrated the microtubule-stabilizing mechanism of the epothilones.

Microtubule formation involves the polymerization of a- and ^-tubulin het-erodimer subunits. A dynamic equilibrium between microtubule polymerization and depolymerization is necessary for the appropriate function of the mitotic spindle. Microtubule-stabilizing agents that bind either tubulin subunits or polymerized microtubules disrupt this equilibrium by preventing depolymerization. As a result, normal spindle formation is altered, the cell cycle is arrested at the G2/M phase, and apoptosis occurs (5-9).

The epothilones and taxanes appear to have overlapping binding sites on the ^-subunit of the tubulin protein heterodimer, based on studies showing that epothilones displace paclitaxel from tubulin polymers (10). In addition, epothi-lone-resistant cell lines contain ^-tubulin mutations that map near the taxane-binding site of the docetaxel-tubulin complex, an observation that provides further support for the overlap in binding sites (11). Nevertheless, the absence of strict cross-resistance between taxanes and epothilones, as well as the unique tubulin mutational profiles of taxane-resistant cell lines, suggests that the two classes of agents interact differently with the amino acid residues that constitute their common binding site (3,12,13).

Modifications of the structure of naturally occurring epothilones have yielded multiple biologically active analogues with varying activity and toxicity profiles

(9,10,14-17). The three principal epothilone analogues under active development in breast cancer—ixabepilone (BMS-247550, aza-epothilone), patupilone (EPO906, epothilone B), and KOS-862 (epothilone D)—are reviewed here. The development of two other analogues, ZK-EPO and BMS-310705 (a water-soluble epothilone B analogue), has been put on hold.

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