title: 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.
authors.affiliation: Department of Biology, McGill University, Montreal, Quebec H3A 1B1, Canada.
authors.forename: Michal
authors.initials: M
authors.lastname: Wieczorek
authors.affiliation: Laboratory for Therapeutic Development, Rosalind and Morris Goodman Cancer Research Centre and Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada.
authors.forename: Joseph
authors.initials: J
authors.lastname: Tcherkezian
authors.affiliation: Laboratory for Therapeutic Development, Rosalind and Morris Goodman Cancer Research Centre and Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Bernier
authors.affiliation: Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen PSI, Switzerland.
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Prota
authors.affiliation: Department of Biology, McGill University, Montreal, Quebec H3A 1B1, Canada.
authors.forename: Sami
authors.initials: S
authors.lastname: Chaaban
authors.affiliation: Laboratory for Therapeutic Development, Rosalind and Morris Goodman Cancer Research Centre and Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada.
authors.forename: Yannève
authors.initials: Y
authors.lastname: Rolland
authors.affiliation: Laboratory for Therapeutic Development, Rosalind and Morris Goodman Cancer Research Centre and Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada.
authors.forename: Claude
authors.initials: C
authors.lastname: Godbout
authors.affiliation: McGill SPR-MS Facility, McGill University, Montreal, Quebec H3G 1Y6, Canada.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Hancock
authors.affiliation: Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10561, USA.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Arezzo
authors.affiliation: Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Ozhan
authors.initials: O
authors.lastname: Ocal
authors.affiliation: Department of Biology, McGill University, Montreal, Quebec H3A 1B1, Canada.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Rocha
authors.affiliation: Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen PSI, Switzerland.
authors.forename: Natacha
authors.initials: N
authors.lastname: Olieric
authors.affiliation: Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.|Research Institute of the McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.
authors.forename: Anita
authors.initials: A
authors.lastname: Hall
authors.affiliation: Department of Chemistry and Biochemistry, University of California at Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Ding
authors.affiliation: Laboratory for Therapeutic Development, Rosalind and Morris Goodman Cancer Research Centre and Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Bramoullé
authors.affiliation: Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Annis
authors.affiliation: Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.|Research Institute of the McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.
authors.forename: George
authors.initials: G
authors.lastname: Zogopoulos
authors.affiliation: Department of Chemistry and Biochemistry, University of California at Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Harran
authors.affiliation: Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Wilkie
authors.affiliation: Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Rolf A
authors.initials: RA
authors.lastname: Brekken
authors.affiliation: Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Siegel
authors.affiliation: Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen PSI, Switzerland.
authors.forename: Michel O
authors.initials: MO
authors.lastname: Steinmetz
authors.affiliation: Laboratory for Therapeutic Development, Rosalind and Morris Goodman Cancer Research Centre and Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada.
authors.forename: Gordon C
authors.initials: GC
authors.lastname: Shore
authors.affiliation: Department of Biology, McGill University, Montreal, Quebec H3A 1B1, Canada. gary.brouhard@mcgill.ca anne.roulston@mcgill.ca.
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Brouhard
authors.affiliation: 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.
authors.forename: Anne
authors.initials: A
authors.lastname: Roulston
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D019281:Dimerization; D023281:Genomics; D006801:Humans; D047029:Lactams, Macrocyclic / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008854:Microscopy, Electron; D008870:Microtubules / Q000187:drug effects*; D008938:Mitosis; D009368:Neoplasm Transplantation; D009474:Neurons / Q000187:drug effects*; D010080:Oxazoles / Q000737:chemistry / Q000494:pharmacology*; D014404:Tubulin / Q000737:chemistry; D014747:Vinblastine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D014748:Vinca Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D000077235:Vinorelbine
chemical_list: D000970:Antineoplastic Agents; C000603931:DZ-2384; D047029:Lactams, Macrocyclic; D010080:Oxazoles; D014404:Tubulin; D014748:Vinca Alkaloids; D014747:Vinblastine; D000077235:Vinorelbine