1 research outputs found
The Discovery of Polo-Like Kinase 4 Inhibitors: Design and Optimization of Spiro[cyclopropane-1,3′[3<i>H</i>]indol]-2′(1′<i>H</i>)‑ones as Orally Bioavailable Antitumor Agents
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 (<i>E</i>)-3-((1<i>H</i>-indazol-6-yl)methylene)indolin-2-ones, which are superseded
by the bioisosteric 2-(1<i>H</i>-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 alkene-linked series. The racemic cyclopropane-linked compounds showed PLK4 affinity and antiproliferative
activity comparable to their alkene-linked congeners with improved
physicochemical, ADME, and pharmacokinetic properties. Positive xenograft
results from the MDA-MB-468 human breast cancer xenograft model for
compound <b>18</b> support the investigation of PLK4 inhibitors
as anticancer therapeutics. A PLK4 X-ray co-structure with racemate <b>18</b> revealed preferential binding of the 1<i>R</i>,2<i>S</i> enantiomer to the PLK4 kinase domain