TY - JOUR
T1 - Anti-breast cancer activity of LFM-A13, a potent inhibitor of Polo-like kinase (PLK)
AU - Uckun, Fatih M.
AU - Dibirdik, Ilker
AU - Qazi, Sanjive
AU - Vassilev, Alexei
AU - Ma, Hong
AU - Mao, Chen
AU - Benyumov, Alexey
AU - Emami, Katayoon H.
PY - 2007/1/15
Y1 - 2007/1/15
N2 - Molecular modeling studies led to the identification of LFM-A13 (α-cyano-β-hydroxy-β-methyl-N-(2,5-dibromophenyl)propena mide) 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 IC50 value of 61 μM, 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 PI3Kγ were inhibited (IC50 values >200-500 μM). The mode of Plk3 inhibition by LFM-A13 was competitive with respect to ATP with a Ki value of 7.2 μM 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.
AB - Molecular modeling studies led to the identification of LFM-A13 (α-cyano-β-hydroxy-β-methyl-N-(2,5-dibromophenyl)propena mide) 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 IC50 value of 61 μM, 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 PI3Kγ were inhibited (IC50 values >200-500 μM). The mode of Plk3 inhibition by LFM-A13 was competitive with respect to ATP with a Ki value of 7.2 μM 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.
KW - Cancer
KW - Mitosis
KW - Polo-like kinase
KW - Transgenic mouse
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U2 - 10.1016/j.bmc.2006.10.050
DO - 10.1016/j.bmc.2006.10.050
M3 - Article
C2 - 17098432
AN - SCOPUS:33845415264
SN - 0968-0896
VL - 15
SP - 800
EP - 814
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 2
ER -