title: The discovery of Polo-like kinase 4 inhibitors: design and optimization of spiro[cyclopropane-1,3'[3H]indol]-2'(1'H).ones as orally bioavailable antitumor agents.
abstract: Polo-like kinase 4 (PLK4), a unique member of the polo-like kinase family of serine-threonine kinases, is a master regulator of centriole duplication that is important for maintaining genome integrity. Overexpression of PLK4 is found in several human cancers and is linked with a predisposition to tumorigenesis. Previous efforts to identify potent and efficacious PLK4 inhibitors resulted in the discovery of (E)-3-((1H-indazol-6-yl)methylene)indolin-2-ones, which are superseded by the bioisosteric 2-(1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-ones reported herein. Optimization of this new cyclopropane-linked series was based on a computational model of a PLK4 X-ray structure and SAR attained from the analogous alkenelinked series. The racemic cyclopropane-linked compounds showed PLK4 affinity and antiproliferative activity comparable to their alkene-linked congeners with improved hysicochemical, ADME, and pharmacokinetic properties. Positive xenograft results from the MDA-MB-468 human breast cancer xenograft model for compound 18 support the investigation of PLK4 inhibitors as anticancer therapeutics. A PLK4 X-ray co-structure with racemate 18 revealed preferential binding of the 1R,2S enantiomer to the PLK4 kinase domain.
authors.affiliation: Campbell Family Institute for Breast Cancer Research, University Health Network , TMDT East Tower, MaRS Centre, 101 College Street, Toronto, Ontario MG5 1L7, Canada.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Sampson
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Narendra Kumar
authors.initials: NK
authors.lastname: Patel
authors.forename: Miklos
authors.initials: M
authors.lastname: Feher
authors.forename: Bryan
authors.initials: B
authors.lastname: Forrest
authors.forename: Sze-Wan
authors.initials: SW
authors.lastname: Li
authors.forename: Louise
authors.initials: L
authors.lastname: Edwards
authors.forename: Radoslaw
authors.initials: R
authors.lastname: Laufer
authors.forename: Yunhui
authors.initials: Y
authors.lastname: Lang
authors.forename: Fuqiang
authors.initials: F
authors.lastname: Ban
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: Jacqueline M
authors.initials: JM
authors.lastname: Mason
authors.forename: Xin
authors.initials: X
authors.lastname: Wei
authors.forename: Reza
authors.initials: R
authors.lastname: Kiarash
authors.forename: Erin
authors.initials: E
authors.lastname: Green
authors.forename: Wei
authors.initials: W
authors.lastname: Qiu
authors.forename: Nickolay Y
authors.initials: NY
authors.lastname: Chirgadze
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: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D061986:MCF-7 Cells; D051379:Mice; D008956:Models, Chemical; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D013141:Spiro Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D047428:Protein Kinase Inhibitors; D013141:Spiro Compounds; C456900:indolin-2-one; C490219:PLK4 protein, human; D017346:Protein Serine-Threonine Kinases