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.
Jacqueline M Mason  1 ,  Dan Chi-Chia Lin  1 ,  Xin Wei  1 ,  Yi Che  1 ,  Yi Yao  1 ,  Reza Kiarash  1 ,  David W Cescon  2 ,  Graham C Fletcher  1 ,  Donald E Awrey  1 ,  Mark R Bray  1 ,  Guohua Pan  1 ,  Tak W Mak  3
Affiliations
  • 1. The Campbell Family Institute for Breast Cancer Research, 101 College Street, Toronto, ON M5G 1L7, Canada.
  • 2. The Campbell Family Institute for Breast Cancer Research, 620 University Avenue, Toronto, ON M5G 2M9, Canada.
  • 3. The Campbell Family Institute for Breast Cancer Research, 620 University Avenue, Toronto, ON M5G 2M9, Canada. Electronic address: [email protected].
PMID: 25043604 DOI: 10.1016/j.ccr.2014.05.006
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.

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