Microtubules are essential in rapidly dividing cells where they form the mitotic spindle, an apparatus that ensures proper chromosome segregation during mitosis ( 1, 2). This differential modulation of tubulin results in a potent MTA therapeutic with enhanced safety. 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. X-ray crystallography and electron microscopy studies demonstrate that DZ-2384 causes straightening of curved protofilaments, an effect proposed to favor polymerization of tubulin. 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. It has an unusually high safety margin and lacks neurotoxicity in rats at effective plasma concentrations. We describe DZ-2384, a preclinical compound that exhibits potent antitumor activity in models of multiple cancer types. MTAs bind to and alter the stability of microtubules, causing cell death in mitosis. Microtubule-targeting agents (MTAs) are widely used anticancer agents, but toxicities such as neuropathy limit their clinical use. X-ray crystallography data collection and refinement statistics. Microscopic changes in dorsal root ganglia and sciatic nerves of rats treated with DZ-2384 and docetaxel. Summary of the effects of vinorelbine on mouse bone marrow. Summary of the effects of DZ-2384 on mouse bone marrow. Summary of lethality in Rgs16∷GFP KIC mice and littermates administered DZ-2384. Summary of clinical observations in Rgs∷GFP KIC mice administered DZ-2384 and gemcitabine. Survival of DZ-2384–treated and vinorelbine-treated mice bearing HT-29 tumors. Conjugation of extended side chain 4 with diastereoisomeric diazonamide core structures. Preparation of an extended, multipurpose diazonamide side chain harboring a biotin tag.įig. Axon width of E18 rat cortical neurons treated with DZ-2384 and vinorelbine.įig. The effects of DZ-2384 and vinorelbine on mitotic H1299 cells.įig. Modeled comparison of vinblastine and vinorelbine binding to tubulin.įig. Tubulin oligomer lengths measured during curvature analysis.įig. Model of biotinylated DZ-2384 binding to tubulin in the context of T 2R-TTL.įig. X-ray crystal structure of T 2R-TTL in complex with DZ-2384.įig. DZ-2384 and inactive DZ-2384D compound structures.įig. Functional genomic screen and cell cycle regulation as the DZ-2384 mechanism of action.įig. Body weight change in rats administered DZ-2384 or docetaxel weekly for 4 weeks.įig. Body weights of weanling control and Rgs16∷GFP KIC mice treated with DZ-2384 and gemcitabine on P29.įig. Body weight in murine xenografts after administration of DZ-2384, vinorelbine, or DZ-2384 and gemcitabine.įig. Antitumor efficacy of DZ-2384 in metastatic breast and adult ALL models.įig.
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