title: 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.
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, 101 College Street, Toronto, ON M5G 1L7, Canada.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Mason
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, 101 College Street, Toronto, ON M5G 1L7, Canada.
authors.forename: Dan Chi-Chia
authors.initials: DC
authors.lastname: Lin
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, 101 College Street, Toronto, ON M5G 1L7, Canada.
authors.forename: Xin
authors.initials: X
authors.lastname: Wei
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, 101 College Street, Toronto, ON M5G 1L7, Canada.
authors.forename: Yi
authors.initials: Y
authors.lastname: Che
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, 101 College Street, Toronto, ON M5G 1L7, Canada.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yao
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, 101 College Street, Toronto, ON M5G 1L7, Canada.
authors.forename: Reza
authors.initials: R
authors.lastname: Kiarash
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, 620 University Avenue, Toronto, ON M5G 2M9, Canada.
authors.forename: David W
authors.initials: DW
authors.lastname: Cescon
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, 101 College Street, Toronto, ON M5G 1L7, Canada.
authors.forename: Graham C
authors.initials: GC
authors.lastname: Fletcher
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, 101 College Street, Toronto, ON M5G 1L7, Canada.
authors.forename: Donald E
authors.initials: DE
authors.lastname: Awrey
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, 101 College Street, Toronto, ON M5G 1L7, Canada.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Bray
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, 101 College Street, Toronto, ON M5G 1L7, Canada.
authors.forename: Guohua
authors.initials: G
authors.lastname: Pan
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, 620 University Avenue, Toronto, ON M5G 2M9, Canada. Electronic address: tmak@uhnres.utoronto.ca.
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival; D002502:Centrioles / Q000187:drug effects / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C000592365:2-(3-(4-((2,6-dimethylmorpholino)methyl)styryl)-1H-indazol-6-yl)-5'-methoxyspiro(cyclopropane-1,3'-indolin)-2'-one; D000970:Antineoplastic Agents; D007191:Indazoles; D007211:Indoles; C490219:PLK4 protein, human; D017346:Protein Serine-Threonine Kinases