Discovery of Potent, Selective and Efficacious Aminopyrazole Inhibitors of PLK4

  • J Med Chem. 2025 Dec 11;68(23):25198-25212. doi: 10.1021/acs.jmedchem.5c02200.
Joon Won Jeong  1 ,  Trevor Chang  1 ,  Jeremy M Murray  1 ,  Ryan L Gonciarz  1 ,  Justin M Salvant  1 ,  Andre H St Amant  1 ,  Sanjay Bhattarai  1 ,  Jae H Chang  1 ,  Jo-Ting Chang  1 ,  Dana M Gwinn  1 ,  Christopher Kochansky  1 ,  Rhea Matsuura  1 ,  Leo Mok  1 ,  Nina M Muñoz  1 ,  Andrew G Raub  1 ,  David Shaya  1 ,  Ziqiang Wang  1 ,  Wei Xu  1 ,  Kai S Yang  1 ,  Heather J Finlay  1 ,  Brian A Sherer  1
Affiliations
  • 1. Small Molecule Discovery, Exelixis, Inc., 1851 Harbor Bay Parkway, Alameda, California 94502, United States.
PMID: 41329867 DOI: 10.1021/acs.jmedchem.5c02200
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.

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