2. Academic Validation
  3. Consensus Pharmacological Interactions for PLK2 Inhibitor Identification in Colorectal Cancer Treatment

Consensus Pharmacological Interactions for PLK2 Inhibitor Identification in Colorectal Cancer Treatment

  • J Chem Inf Model. 2026 Jan 12;66(1):577-590. doi: 10.1021/acs.jcim.5c02197.
Yi-Wen Wu 1,  Chun-Lin Yang 1,  Tony Eight Lin 1 2,  Yun-Hsuan Yeh 1,  Yu-Ting Fang-Chin 1 2,  Tzu-Ying Sung 1,  Shih-Chung Yen 3,  Jui-Hua Hsieh 4,  Cheng-Chih Chung 5 6,  Shiow-Lin Pan 1 2 7,  Kai-Cheng Hsu 1 2 7 8
Affiliations

Affiliations

  • 1 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
  • 2 Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
  • 3 Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong (Shenzhen), Shenzhen, Guangdong 518172, China.
  • 4 Division of Translational Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Durham, North Carolina 27709, United States.
  • 5 Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
  • 6 Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan.
  • 7 TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan.
  • 8 Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan.
PMID: 41405409 DOI: 10.1021/acs.jcim.5c02197
Abstract

PLK2 plays a critical role in cellular stress response, redox regulation, and tumor progression. In colorectal Cancer (CRC), elevated PLK2 expression is associated with chemoresistance and poor patient prognosis, making it a compelling target for therapeutic intervention. In this study, we used a structure-based drug discovery strategy to develop a consensus model incorporating pharmacological interactions from various PLK2 structures. This model enhanced the hit rate for identifying inhibitors during virtual screening, increasing the ROC-AUC from 0.906 to 0.930. We then used the model to screen the ChemDiv compound library and identified two novel PLK2 inhibitors. Next, we searched for analogs of the most potent compound and evaluated their activity. Two analogs demonstrated submicromolar inhibition, including Y207-5465 (IC50: 584.3 nM) and 8012-3246 (IC50: 774.5 nM). Structure-activity relationship (SAR) analysis was performed to identify key interactions contributing to potency. In vitro assays demonstrated that 8012-3246 exhibited better cytotoxicity (IC50: 7.97 and 17.67 μM) and antiproliferative effects (GI50: 3.28 and 6.62 μM) in HT-29 and HCT-116 CRC cell lines, respectively. Kinase profiling confirmed that 8012-3246 possesses high selectivity for PLK2. Mechanistic studies further revealed that 8012-3246 inhibited GSK3β phosphorylation, a key downstream effector of PLK2 involved in redox homeostasis and cell survival. These findings support the use of pharmacological consensus modeling to identify novel PLK2 inhibitors and highlight PLK2 inhibition as a promising strategy for CRC treatment.

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