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UA62784 Is a cytotoxic inhibitor of microtubules, not CENP-E.

Abstract
A recent screen for compounds that selectively targeted pancreatic cancer cells isolated UA62784. We found that UA62784 inhibits microtubule polymerization in vitro. UA62784 interacts with tubulin dimers ten times more potently than colchicine, vinblastine, or nocodazole. Competition experiments revealed that UA62784 interacts with tubulin at or near the colchicine-binding site. Nanomolar doses of UA62784 promote the accumulation of mammalian cells in mitosis, due to aberrant mitotic spindles, as shown by immunofluorescence and live cell imaging. Treatment of cancerous cell lines with UA62784 is lethal, following activation of apoptosis signaling. By monitoring mitotic spindle perturbations and apoptosis, we found that the effects of UA62784 and of some known microtubule-depolymerizing drugs are additive. Finally, high content screening of H2B-GFP HeLa cells revealed that low doses of UA62784 and vinblastine potentiate each other to inhibit proliferation.
AuthorsSergey Tcherniuk, Sébastien Deshayes, Vasiliki Sarli, Gilles Divita, Ariane Abrieu
JournalChemistry & biology (Chem Biol) Vol. 18 Issue 5 Pg. 631-41 (May 27 2011) ISSN: 1879-1301 [Electronic] United States
PMID21609844 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2011 Elsevier Ltd. All rights reserved.
Chemical References
  • Chromosomal Proteins, Non-Histone
  • Oxazoles
  • Tubulin
  • Tubulin Modulators
  • UA 62784
  • Xanthones
  • centromere protein E
  • Vinblastine
  • Nocodazole
  • Colchicine
Topics
  • Apoptosis
  • Binding Sites
  • Chromosomal Proteins, Non-Histone (antagonists & inhibitors, metabolism)
  • Colchicine (pharmacology)
  • Dimerization
  • HeLa Cells
  • Humans
  • Microtubules (drug effects)
  • Mitosis
  • Nocodazole (pharmacology)
  • Oxazoles (chemistry, toxicity)
  • Spindle Apparatus (drug effects)
  • Tubulin (chemistry, metabolism)
  • Tubulin Modulators (chemistry, toxicity)
  • Vinblastine (pharmacology)
  • Xanthones (chemistry, toxicity)

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