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Indibulin, a Novel Microtubule Inhibitor, Discriminates between Mature Neuronal and Nonneuronal Tubulin

¹ University of Luxembourg, Luxembourg City, Luxembourg and ² Department of Cancer Research, ASTA Medica AG, Frankfurt am Main, Germany

Requests for reprints: Gerald Bacher, MondoGen AG, Muergstrasse 18, 6370 Stans, Switzerland. Phone: 41-793719184; Fax: 49-84938931; E-mail: gerald.bacher{at}mondobiotech.com.

Key Words: microtubule inhibitor • destabilization of microtubules • neurotoxicity • posttranslationally modified tubulin • antitumoral efficacy

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. [Cancer Res 2009;69(1):171–7]