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 <b>25</b>, 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 <b>25</b> in a CHP-134 neuroblastoma xenograft tumor model.
Authors
- Jae Hoon Chang (ORCID: https://orcid.org/0000-0003-3457-7695)
- Dana M. Gwinn (ORCID: https://orcid.org/0009-0003-8650-0224)
- Trevor Chang
- Brian Sherer
- André H. St. Amant (ORCID: https://orcid.org/0000-0002-4842-1918)
- Jeremy M. Murray (ORCID: https://orcid.org/0000-0002-2161-9326)
- Sanjay Bhattarai (ORCID: https://orcid.org/0000-0001-8753-5662)
- Christopher J. Kochansky
- Ryan L. Gonciarz (ORCID: https://orcid.org/0000-0002-6600-7032)
- Justin M. Salvant (ORCID: https://orcid.org/0000-0001-8359-8105)
- Leo Mok
- Ziqiang Wang (ORCID: https://orcid.org/0009-0006-4490-9322)
- Jo-Ting Chang (ORCID: https://orcid.org/0009-0004-4993-862X)
- Heather J. Finlay (ORCID: https://orcid.org/0000-0003-2309-0136)
- Nina M. Muñoz (ORCID: https://orcid.org/0000-0001-7733-4883)
- Rieko Matsuura (ORCID: https://orcid.org/0009-0005-5657-3996)
- Wei Xu (ORCID: https://orcid.org/0000-0002-7834-0086)
- Kai S. Yang (ORCID: https://orcid.org/0000-0002-1890-4169)
- Joon Won Jeong (ORCID: https://orcid.org/0009-0009-1138-6870)
- David Shaya (ORCID: https://orcid.org/0009-0009-1389-9194)
- Andrew G. Raub
Institutions
- Exelixis (United States) (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-12-02
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c02200
- Primary Topic
- Microtubule and mitosis dynamics
- Type
- article
- Field-Weighted Citation Impact
- 0.00