Functional characterization of CFI-400945, a Polo-like kinase 4 inhibitor, as a potential anticancer agent

Cancer Cell. 2014 Aug 11;26(2):163-76. doi: 10.1016/j.ccr.2014.05.006. Epub 2014 Jul 17.

Abstract

PLK4 was identified as a promising therapeutic target through a systematic approach that combined RNAi screening with gene expression analysis in human breast cancers and cell lines. A drug discovery program culminated in CFI-400945, a potent and selective PLK4 inhibitor. Cancer cells treated with CFI-400945 exhibit effects consistent with PLK4 kinase inhibition, including dysregulated centriole duplication, mitotic defects, and cell death. Oral administration of CFI-400945 to mice bearing human cancer xenografts results in the significant inhibition of tumor growth at doses that are well tolerated. Increased antitumor activity in vivo was observed in PTEN-deficient compared to PTEN wild-type cancer xenografts. Our findings provide a rationale for the clinical evaluation of CFI-400945 in patients with solid tumors, in particular those deficient in PTEN.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Survival
  • Centrioles / drug effects
  • Centrioles / metabolism
  • Female
  • Gene Expression
  • Gene Knockdown Techniques
  • Humans
  • Indazoles / pharmacology*
  • Indoles / pharmacology*
  • Inhibitory Concentration 50
  • Mice
  • Mice, Inbred NOD
  • Mice, Nude
  • Mice, SCID
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • 2-(3-(4-((2,6-dimethylmorpholino)methyl)styryl)-1H-indazol-6-yl)-5'-methoxyspiro(cyclopropane-1,3'-indolin)-2'-one
  • Antineoplastic Agents
  • Indazoles
  • Indoles
  • PLK4 protein, human
  • Protein-Serine-Threonine Kinases