Linked Life Data

17098432

Source:http://linkedlifedata.com/resource/pubmed/id/17098432

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2006-12-15
pubmed:abstractText
Molecular modeling studies led to the identification of LFM-A13 (alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl)propenamide) as a potent inhibitor of Polo-like kinase (Plk). LFM-A13 inhibited recombinant purified Plx1, the Xenopus homolog of Plk, in a concentration-dependent fashion, as measured by autophosphorylation and phosphorylation of a substrate Cdc25 peptide. LFM-A13 was a selective Plk inhibitor. While the human PLK3 kinase was also inhibited by LFM-A13 with an IC(50) value of 61 microM, none of the 7 other serine/threonine kinases, including CDK1, CDK2, CDK3, CHK1, IKK, MAPK1 or SAPK2a, none of the 10 tyrosine kinases, including ABL, BRK, BMX, c-KIT, FYN, IGF1R, PDGFR, JAK2, MET, or YES, or the lipid kinase PI3Kgamma were inhibited (IC(50) values >200-500 microM). The mode of Plk3 inhibition by LFM-A13 was competitive with respect to ATP with a K(i) value of 7.2 microM from Dixon plots. LFM-A13 blocked the cell division in a zebrafish (ZF) embryo model at the 16-cell stage of the embryonic development followed by total cell fusion and lysis. LFM-A13 prevented bipolar mitotic spindle assembly in human breast cancer cells and glioblastoma cells and when microinjected into living epithelial cells at the prometaphase stage of cell division, it caused a total mitotic arrest. Notably, LFM-A13-delayed tumor progression in the MMTV/neu transgenic mouse model of HER2 positive breast cancer at least as effectively as paclitaxel and gemcitabine. LFM-A13 showed a favorable toxicity profile in mice and rats. In particular there was no evidence of hematologic toxicity as documented by peripheral blood counts and bone marrow examinations. These results establish LFM-A13 as a small molecule inhibitor of Plk with in vitro and in vivo anti-proliferative activity against human breast cancer.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
0968-0896
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
15
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
800-14
pubmed:dateRevised
2011-11-2
pubmed:meshHeading
pubmed-meshheading:17098432-Amides, pubmed-meshheading:17098432-Animals, pubmed-meshheading:17098432-Antineoplastic Agents, pubmed-meshheading:17098432-Breast Neoplasms, pubmed-meshheading:17098432-Cell Cycle Proteins, pubmed-meshheading:17098432-Cell Line, Tumor, pubmed-meshheading:17098432-Cell Proliferation, pubmed-meshheading:17098432-DNA, Recombinant, pubmed-meshheading:17098432-Disease Progression, pubmed-meshheading:17098432-Drug Screening Assays, Antitumor, pubmed-meshheading:17098432-Enzyme Inhibitors, pubmed-meshheading:17098432-Female, pubmed-meshheading:17098432-Fluorescence, pubmed-meshheading:17098432-Humans, pubmed-meshheading:17098432-Mice, pubmed-meshheading:17098432-Mice, Inbred BALB C, pubmed-meshheading:17098432-Mice, Transgenic, pubmed-meshheading:17098432-Microinjections, pubmed-meshheading:17098432-Microscopy, Confocal, pubmed-meshheading:17098432-Models, Molecular, pubmed-meshheading:17098432-Nitriles, pubmed-meshheading:17098432-Protein-Serine-Threonine Kinases, pubmed-meshheading:17098432-Proto-Oncogene Proteins, pubmed-meshheading:17098432-Rats, pubmed-meshheading:17098432-Zebrafish
pubmed:year
2007
pubmed:articleTitle
Anti-breast cancer activity of LFM-A13, a potent inhibitor of Polo-like kinase (PLK).
pubmed:affiliation
Paradigm Pharmaceuticals, 2139 4th Street, White Bear Lake, MN 55110, USA. fatih_uckun@ih.org
pubmed:publicationType
Journal Article