The Discovery of Polo-Like Kinase 4 Inhibitors: Identification of (1R,2S)-2-(3((E)-4-(((cis)-2,6-Dimethylmorpholino)methyl)styryl)-1H-indazol-6-yl)-5 '-methoxyspiro[cyclopropane-1,3 '-indolin]-2 '-one (CFI-400945) as a Potent, Orally Active Antitumor Agent
Sampson, PB; Liu, Y; Forrest, B; Cumming, G; Li, SzeWan; Patel, NK; Edwards, L; Laufer, R; Feher, M; Ban, F; Awrey, DE; Mao, G; Plotnikova, O; Hodgson, R; Beletskaya, I; Mason, JM; Luo, X; Nadeem, V; Wei, Xin; Kiarash, R; Madeira, B; Huang, P; Mak, TakW; Pan, G; Pauls, HW
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efficacious PLK4 inhibitors resulted in the discovery of (E)-3-((1H-indazol-6-yl)methylene)indolin-2-ones, which are superseded by the bioisosteric 2-(1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-ones reported herein.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.