Discovery of Potent, Selective and Efficacious Aminopyrazole Inhibitors of PLK4

Abstract 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.