The Discovery
of PLK4 Inhibitors: (<i>E</i>)‑3-((1<i>H</i>‑Indazol-6-yl)methylene)indolin-2-ones
as Novel Antiproliferative Agents
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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 (<i>E</i>)-3-((1<i>H</i>-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 <b>50</b> (designated CFI-400437) support the potential
of these novel PLK4 inhibitors for cancer therapy