Research ArticleCancer

The synthetic diazonamide DZ-2384 has distinct effects on microtubule curvature and dynamics without neurotoxicity

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Science Translational Medicine  16 Nov 2016:
Vol. 8, Issue 365, pp. 365ra159
DOI: 10.1126/scitranslmed.aag1093

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Throwing a curve ball to cancer

Drugs such as vinca alkaloids, which target tubulin and interfere with microtubule function in mitosis, are commonly used for the treatment of cancer. Unfortunately, they also damage microtubules in normal undividing cells including neurons, resulting in toxicity. Wieczorek et al. identified a drug called DZ-2384, which may offer a safer alternative to the vincas. The authors found that although DZ-2384 is very effective at targeting cancer cells by inhibiting mitosis, it preserves the microtubule network in non-dividing cells and in primary neurons at effective doses and is much safer in mouse models. By analyzing the structure of tubulin with different compounds, the authors determined that DZ-2384 binds at the vinca site but induces a distinctive change in the curvature of growing tubulin protofilaments, which may explain its unusual effects on microtubule dynamics and decreased toxicity.

Abstract

Microtubule-targeting agents (MTAs) are widely used anticancer agents, but toxicities such as neuropathy limit their clinical use. MTAs bind to and alter the stability of microtubules, causing cell death in mitosis. We describe DZ-2384, a preclinical compound that exhibits potent antitumor activity in models of multiple cancer types. It has an unusually high safety margin and lacks neurotoxicity in rats at effective plasma concentrations. DZ-2384 binds the vinca domain of tubulin in a distinct way, imparting structurally and functionally different effects on microtubule dynamics compared to other vinca-binding compounds. X-ray crystallography and electron microscopy studies demonstrate that DZ-2384 causes straightening of curved protofilaments, an effect proposed to favor polymerization of tubulin. Both DZ-2384 and the vinca alkaloid vinorelbine inhibit microtubule growth rate; however, DZ-2384 increases the rescue frequency and preserves the microtubule network in nonmitotic cells and in primary neurons. This differential modulation of tubulin results in a potent MTA therapeutic with enhanced safety.

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