Consensus Pharmacological Interactions for PLK2 Inhibitor Identification in Colorectal Cancer Treatment.

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.