Tasidotin (ILX-651), an orally active synthetic microtubule-targeted derivative of the marine
depsipeptide dolastatin-15, is currently undergoing clinical evaluation for
cancer treatment.
Tasidotin inhibited proliferation of MCF7/GFP
breast cancer cells with an IC(50) of 63 nmol/L and inhibited mitosis with an IC(50) of 72 nmol/L in the absence of detectable effects on spindle microtubule
polymer mass.
Tasidotin inhibited the polymerization of purified
tubulin into microtubules weakly (IC(50) approximately 30 micromol/L). However, it strongly suppressed the dynamic instability behavior of the microtubules at their plus ends at concentrations approximately 5 to 10 times below those required to inhibit polymerization. Its major actions were to reduce the shortening rate, the switching frequency from growth to shortening (catastrophe frequency), and the fraction of time the microtubules grew. In contrast with all other microtubule-targeted drugs thus far examined that can inhibit polymerization,
tasidotin did not inhibit the growth rate. In contrast to stabilizing plus ends,
tasidotin enhanced microtubule dynamic instability at minus ends, increasing the shortening length, the fraction of time the microtubules shortened, and the catastrophe frequency and reducing the rescue frequency.
Tasidotin C-carboxylate, the major intracellular metabolite of
tasidotin, altered dynamic instability of purified microtubules in a qualitatively similar manner to
tasidotin but was 10 to 30 times more potent. The results suggest that the principal mechanism by which
tasidotin inhibits cell proliferation is by suppressing spindle microtubule dynamics.
Tasidotin may be a relatively weak
prodrug for the functionally active
tasidotin C-carboxylate.