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

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.

The compound millepachine and its derivatives inhibit tubulin polymerization by irreversibly binding to the colchicine-binding site in β-tubulin

“…Tubulin inhibitors are commonly used chemotherapeutic agents for cancer therapy (3,4,30). Most tubulin inhibitors used in clinical were targeted to paclitaxel or vinblastine sites, such as paclitaxel, docetaxel, vinblastine, vincristine, vinorelbine, and eribulin (31)(32)(33)(34). However, tubulin inhibitors binding to the colchicine site (the first discovered tubulin inhibitor site) (15,30) are not used in clinical cancer therapy (15), although colchicine site tubulin inhibitors have obvious advantages over other tubulin inhibitors, such as having simple structure, being MDs irreversibly bind to colchicine site easy to synthesize, not being the substrate of multidrug-resistance protein, and not being easy to produce drug resistance (15).…”

Recent Progress of Marine Polypeptides as Anticancer Agents

“…The growth rate of microtubules was inhibited by DZ-2384. However, study has reported that DZ-2384 increased the rescue frequency and preserves the microtubule network in nonmitotic cells and primary neurons [71]. BF65 and BF78 derived from Hemiasterlin are highly effective in killing cancer cell at the concentrations of nanomolar range through the inhibition of tubulin polymerization, similar to the effect of vinca alkaloids [72].…”

“…Studies have indicated that some of the compositions are effective in the treatment of proliferative diseases such as cancer (US7538129) [70]. The synthetic diazonamide analogue, DZ-2384 showed strong anticancer activity at effective plasma concentrations against various of cancers with high safety margin without neurotoxicity in rats [71]. Compared to other vinca-binding compounds, DZ-2384 binds to the vinca domain of tubulin in a distinct way, impairing structural and functional microtubule dynamics.…”

From Seabed to Bedside: A Review on Promising Marine Anticancer Compounds

“…Diazonamide, also named DZ-2384, exhibited potent antitumor activity in models of multiple cancer types and lacked neurotoxicity in rats. Diazonamide binds the vinca domain of tubulin, causing the straightening of curved protofilaments [79].…”