PUBLICATION
Anti-breast cancer activity of LFM-A13, a potent inhibitor of Polo-like kinase (PLK)
- Authors
- Uckun, F.M., Dibirdik, I., Qazi, S., Vassilev, A., Ma, H., Mao, C., Benyumov, A., and Emami, K.H.
- ID
- ZDB-PUB-061116-12
- Date
- 2007
- Source
- Bioorganic & Medicinal Chemistry 15(2): 800-814 (Journal)
- Registered Authors
- Benyumov, Alexey O.
- Keywords
- Polo-like kinase, Mitosis, Transgenic mouse, Cancer
- MeSH Terms
-
- Amides/chemical synthesis*
- Amides/pharmacology*
- Amides/toxicity
- Animals
- Antineoplastic Agents/chemical synthesis*
- Antineoplastic Agents/pharmacology*
- Breast Neoplasms/drug therapy*
- Breast Neoplasms/pathology
- Cell Cycle Proteins/antagonists & inhibitors*
- Cell Line, Tumor
- Cell Proliferation/drug effects
- DNA, Recombinant/chemical synthesis
- DNA, Recombinant/pharmacology
- Disease Progression
- Drug Screening Assays, Antitumor
- Enzyme Inhibitors/chemical synthesis*
- Enzyme Inhibitors/pharmacology*
- Female
- Fluorescence
- Humans
- Mice
- Mice, Inbred BALB C
- Mice, Transgenic
- Microinjections
- Microscopy, Confocal
- Models, Molecular
- Nitriles/chemical synthesis*
- Nitriles/pharmacology*
- Nitriles/toxicity
- Protein Serine-Threonine Kinases/antagonists & inhibitors*
- Proto-Oncogene Proteins/antagonists & inhibitors*
- Rats
- Zebrafish
- PubMed
- 17098432 Full text @ Bioorg. Med. Chem.
Citation
Uckun, F.M., Dibirdik, I., Qazi, S., Vassilev, A., Ma, H., Mao, C., Benyumov, A., and Emami, K.H. (2007) Anti-breast cancer activity of LFM-A13, a potent inhibitor of Polo-like kinase (PLK). Bioorganic & Medicinal Chemistry. 15(2):800-814.
Abstract
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 61muM, 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 >200-500muM). The mode of Plk3 inhibition by LFM-A13 was competitive with respect to ATP with a K(i) value of 7.2muM 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping