Functional Characterization of CFI-400945, a Polo-like Kinase 4 Inhibitor, as a Potential Anticancer Agent

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.

The benefits of local depletion: The centrosome as a scaffold for ubiquitin-proteasome-mediated degradation

“…43,44 Given that Plk4 is overexpressed in over a quarter of human tumors, it is rapidly emerging as a potential cancer target, and suppression of Plk4 reduces cell proliferation in a number of breast cancer cell lines. 45 A more comprehensive understanding of centrosome-specific degradation pathways may allow for novel therapeutic strategies that modulate degradation of substrates specifically at the centrosome without disrupting the bulk of total cellular ubiquitin-proteasomal degradation.…”

Fighting Fire with Fire in Cancer

“…In vitro treatment of human cancer cells with CFI-400945 results in effects similar to those of siRNA-mediated PLK4 kinase inhibition, including mitotic defects, centriole duplication, and cell death [57]. In in vivo mouse models based on human ovarian or breast cancer xenografts, tumor growth was significantly inhibited by CFI-400945 in a manner influenced by the PTEN status of the tumor [57]. PTEN-deficient xenografts showed a greater response to CFI-400945 than xenografts expressing wild type PTEN, making PTEN status a potential predictive biomarker for therapy with this first-in-class agent [57].…”

“…By using a systematic approach that combines RNAi screening with gene expression analysis in human breast cancers and cell lines and focusing on cancer cell aneuploidy, we have identified polo-like kinase-4 (PLK4), an enzyme critical for aneuploidy maintenance, as a promising therapeutic target [57]. A drug discovery program culminated in the isolation of CFI-400945, a potent and selective smallmolecule PLK4 inhibitor [57].…”

“…A drug discovery program culminated in the isolation of CFI-400945, a potent and selective smallmolecule PLK4 inhibitor [57]. In vitro treatment of human cancer cells with CFI-400945 results in effects similar to those of siRNA-mediated PLK4 kinase inhibition, including mitotic defects, centriole duplication, and cell death [57].…”

“…A drug discovery program culminated in the isolation of CFI-400945, a potent and selective smallmolecule PLK4 inhibitor [57]. In vitro treatment of human cancer cells with CFI-400945 results in effects similar to those of siRNA-mediated PLK4 kinase inhibition, including mitotic defects, centriole duplication, and cell death [57]. In in vivo mouse models based on human ovarian or breast cancer xenografts, tumor growth was significantly inhibited by CFI-400945 in a manner influenced by the PTEN status of the tumor [57].…”