title: The discovery of PLK4 inhibitors: (E)-3-((1H-Indazol-6-yl)methylene)indolin-2-ones as novel antiproliferative agents.
abstract: The family of Polo-like kinases is important in the regulation of mitotic progression; this work keys on one member, namely Polo-like kinase 4 (PLK4). PLK4 has been identified as a candidate anticancer target which prompted a search for potent and selective inhibitors of PLK4. The body of the paper describes lead generation and optimization work which yielded nanomolar PLK4 inhibitors. Lead generation began with directed virtual screening, using a ligand-based focused library and a PLK4 homology model. Validated hits were used as starting points for the design and discovery of PLK4 inhibitors of novel structure, namely (E)-3-((1H-indazol-6-yl)methylene)indolin-2-ones. Computational models, based on a published X-ray structure (PLK4 kinase domain), were used to understand and optimize the in vitro activity of the series; potent antiproliferative activity was obtained. The kinase selectivity profile and cell cycle analysis of selected inhibitors are described. The results of a xenograft study with an optimized compound 50 (designated CFI-400437) support the potential of these novel PLK4 inhibitors for cancer therapy.
authors.affiliation: Campbell Family Institute for Breast Cancer Research, TMDT East Tower, MaRS Centre, 101 College Street, Toronto, Ontario MG5 1L7, Canada.
authors.forename: Radoslaw
authors.initials: R
authors.lastname: Laufer
authors.forename: Bryan
authors.initials: B
authors.lastname: Forrest
authors.forename: Sze-Wan
authors.initials: SW
authors.lastname: Li
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Peter
authors.initials: P
authors.lastname: Sampson
authors.forename: Louise
authors.initials: L
authors.lastname: Edwards
authors.forename: Yunhui
authors.initials: Y
authors.lastname: Lang
authors.forename: Donald E
authors.initials: DE
authors.lastname: Awrey
authors.forename: Guodong
authors.initials: G
authors.lastname: Mao
authors.forename: Olga
authors.initials: O
authors.lastname: Plotnikova
authors.forename: Genie
authors.initials: G
authors.lastname: Leung
authors.forename: Richard
authors.initials: R
authors.lastname: Hodgson
authors.forename: Irina
authors.initials: I
authors.lastname: Beletskaya
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Mason
authors.forename: Xunyi
authors.initials: X
authors.lastname: Luo
authors.forename: Xin
authors.initials: X
authors.lastname: Wei
authors.forename: Yi
authors.initials: Y
authors.lastname: Yao
authors.forename: Miklos
authors.initials: M
authors.lastname: Feher
authors.forename: Fuqiang
authors.initials: F
authors.lastname: Ban
authors.forename: Reza
authors.initials: R
authors.lastname: Kiarash
authors.forename: Erin
authors.initials: E
authors.lastname: Green
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: Guohua
authors.initials: G
authors.lastname: Pan
authors.forename: Henry W
authors.initials: HW
authors.lastname: Pauls
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005260:Female; D007191:Indazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D016513:Mice, SCID; D008958:Models, Molecular; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D007191:Indazoles; D007211:Indoles; C490219:PLK4 protein, human; D017346:Protein Serine-Threonine Kinases