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Sci Transl Med. 2016 Nov 16;8(365):365ra159.

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

Author information

1
Department of Biology, McGill University, Montreal, Quebec H3A 1B1, Canada.
2
Laboratory for Therapeutic Development, Rosalind and Morris Goodman Cancer Research Centre and Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada.
3
Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen PSI, Switzerland.
4
McGill SPR-MS Facility, McGill University, Montreal, Quebec H3G 1Y6, Canada.
5
Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10561, USA.
6
Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
7
Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
8
Research Institute of the McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.
9
Department of Chemistry and Biochemistry, University of California at Los Angeles, Los Angeles, CA 90095, USA.
10
Department of Biology, McGill University, Montreal, Quebec H3A 1B1, Canada. gary.brouhard@mcgill.ca anne.roulston@mcgill.ca.
11
Laboratory for Therapeutic Development, Rosalind and Morris Goodman Cancer Research Centre and Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada. gary.brouhard@mcgill.ca anne.roulston@mcgill.ca.

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.

PMID:
27856798
PMCID:
PMC5291303
DOI:
10.1126/scitranslmed.aag1093
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Diazon Pharmaceuticals Inc. holds the rights to the Patent Cooperation Treaty publication no. WO2009/134938 that covers DZ-2384. None of the authors of this manuscript are named inventors on this patent. G.C.S., A.R., and P.H. are founders and shareholders in Diazon Pharmaceuticals Inc. R.A.B. and T.M.W. are founders of Tuevol Therapeutics Inc. and are inventors on patent applications (62/067,304; 62/067,276; 62/232,901; and 62/232,922) held or submitted by the UT Southwestern Medical Center that cover the use of the GEMM rapid in vivo assay (Rgs16∷GFP;KIC model) for screening therapeutics for pancreatic ductal adenocarcinoma.

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