title: ELR510444, a novel microtubule disruptor with multiple mechanisms of action.
abstract: Although several microtubule-targeting drugs are in clinical use, there remains a need to identify novel agents that can overcome the limitations of current therapies, including acquired and innate drug resistance and undesired side effects. In this study, we show that ELR510444 has potent microtubule-disrupting activity, causing a loss of cellular microtubules and the formation of aberrant mitotic spindles and leading to mitotic arrest and apoptosis of cancer cells. ELR510444 potently inhibited cell proliferation with an IC(50) value of 30.9 nM in MDA-MB-231 cells, inhibited the rate and extent of purified tubulin assembly, and displaced colchicine from tubulin, indicating that the drug directly interacts with tubulin at the colchicine-binding site. ELR510444 is not a substrate for the P-glycoprotein drug transporter and retains activity in βIII-tubulin-overexpressing cell lines, suggesting that it circumvents both clinically relevant mechanisms of drug resistance to this class of agents. Our data show a close correlation between the concentration of ELR510444 required for inhibition of cellular proliferation and that required to cause significant loss of cellular microtubule density, consistent with its activity as a microtubule depolymerizer. ELR510444 also shows potent antitumor activity in the MDA-MB-231 xenograft model with at least a 2-fold therapeutic window. Studies in tumor endothelial cells show that a low concentration of ELR510444 (30 nM) rapidly alters endothelial cell shape, similar to the effect of the vascular disrupting agent combretastatin A4. These results suggest that ELR510444 is a novel microtubule-disrupting agent with potential antivascular effects and in vivo antitumor efficacy.
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: Risinger
authors.forename: C D
authors.initials: CD
authors.lastname: Westbrook
authors.forename: A
authors.initials: A
authors.lastname: Encinas
authors.forename: M
authors.initials: M
authors.lastname: Mülbaier
authors.forename: C M
authors.initials: CM
authors.lastname: Schultes
authors.forename: S
authors.initials: S
authors.lastname: Wawro
authors.forename: J D
authors.initials: JD
authors.lastname: Lewis
authors.forename: B
authors.initials: B
authors.lastname: Janssen
authors.forename: F J
authors.initials: FJ
authors.lastname: Giles
authors.forename: S L
authors.initials: SL
authors.lastname: Mooberry
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008870:Microtubules / Q000187:drug effects* / Q000502:physiology*; D008938:Mitosis / Q000187:drug effects / Q000502:physiology; D051381:Rats; D008941:Spindle Apparatus / Q000187:drug effects / Q000502:physiology; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology*; D013552:Swine; D013876:Thiophenes / Q000737:chemistry* / Q000494:pharmacology*; D050257:Tubulin Modulators / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C557643:ELR 510444; D013449:Sulfonamides; D013876:Thiophenes; D050257:Tubulin Modulators