title: Blocking Blood Flow to Solid Tumors by Destabilizing Tubulin: An Approach to Targeting Tumor Growth.
abstract: The unique characteristics of the tumor vasculature offer the possibility to selectively target tumor growth and vascularization using tubulin-destabilizing agents. Evidence accumulated with combretastatin A-4 (CA-4) and its prodrug CA-4P support the therapeutic value of compounds sharing this mechanism of action. However, the chemical instability and poor solubility of CA-4 demand alternative compounds that are able to surmount these limitations. This Perspective illustrates the different classes of compounds that behave similar to CA-4, analyzes their binding mode to αβ-tubulin according to recently available structural complexes, and includes described approaches to improve their delivery. In addition, dissecting the mechanism of action of CA-4 and analogues allows a closer insight into the advantages and drawbacks associated with these tubulin-destabilizing agents that behave as vascular disrupting agents (VDAs).
authors.affiliation: Instituto de Química Médica (IQM-CSIC) , Juan de la Cierva 3, E-28006 Madrid, Spain.
authors.forename: María-Jesús
authors.initials: MJ
authors.lastname: Pérez-Pérez
authors.affiliation: Instituto de Química Médica (IQM-CSIC) , Juan de la Cierva 3, E-28006 Madrid, Spain.
authors.forename: Eva-María
authors.initials: EM
authors.lastname: Priego
authors.affiliation: Instituto de Química Médica (IQM-CSIC) , Juan de la Cierva 3, E-28006 Madrid, Spain.
authors.forename: Oskía
authors.initials: O
authors.lastname: Bueno
authors.affiliation: Rega Institute for Medical Research, KU Leuven , B-3000 Leuven, Belgium.
authors.forename: Maria Solange
authors.initials: MS
authors.lastname: Martins
authors.affiliation: Instituto de Química Médica (IQM-CSIC) , Juan de la Cierva 3, E-28006 Madrid, Spain.
authors.forename: María-Dolores
authors.initials: MD
authors.lastname: Canela
authors.affiliation: Rega Institute for Medical Research, KU Leuven , B-3000 Leuven, Belgium.
authors.forename: Sandra
authors.initials: S
authors.lastname: Liekens
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001632:Bibenzyls / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D055808:Drug Discovery / Q000379:methods; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D001632:Bibenzyls; D014404:Tubulin; D050257:Tubulin Modulators; C040105:combretastatin