Discovery of Potent, Selective and Efficacious Aminopyrazole Inhibitors of PLK4

Polo-like
kinase 4 (PLK4) is a therapeutic target of high interest
due to its essential role in mitotic regulation and centriole duplication.
Recently, centriole depletion driven by PLK4 inhibition has been identified
as a synthetically lethal target for cancers with elevated TRIM37
expression. Herein, we disclose the discovery of 25,
a potent and selective PLK4 inhibitor. A validated hit from high-throughput
screening of our compound library provided the starting point for
further optimization. Structural analysis of multiple X-ray cocrystal
structures enabled the design of analogs that demonstrated excellent
kinome selectivity. Tumor regression was observed in efficacy studies
of compound 25 in a CHP-134 neuroblastoma xenograft tumor
model.