Microtubule inhibitors interfere with microtubule dynamics, causing cell cycle arrest and apoptosis. These effects are responsible for the chemotherapeutic activities of members of the
taxane and Vinca
alkaloid families in oncology. Unfortunately, a major side effect of the
taxanes and
Vinca alkaloids is the development of
peripheral neuropathies.
Indibulin (N-[pyridin-4-yl]-[1-(4-chlorbenzyl)-indol-3-yl]-glyoxyl-amid;
D-24851; ZIO-301), a novel synthetic small molecule microtubule inhibitor, destabilizes microtubules and has antitumor activity but does not exhibit neurotoxicity in preclinical animal studies. In the present study, it has been found that
indibulin is able to discriminate between highly posttranslationally modified
tubulin present in mature neuronal microtubules, and less-modified
tubulin present in immature neuronal or nonneuronal microtubules.
Vincristine and
colchicine act on either
tubulin equally well. The binding site of
indibulin on mature neuronal microtubules seems to be inaccessible due to the posttranslational modifications, a theory that is supported by the observation that
indibulin did not disrupt the integrity of highly modified microtubules present in neurites of
pheochromocytoma (PC12) cells. The specificity of
indibulin for unmodified microtubules seems to be dependent on the pyridyl moiety of
indibulin because derivatives that have the pyridyl moiety replaced are not able to discriminate between highly and less-modified tubulins. The observed broad antitumor activity of
indibulin and the lack of central and peripheral nervous system toxicity in preclinical studies make it a promising candidate for development as a
cancer treatment.
Indibulin is currently in phase I clinical trials.