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

## TL;DR

This study identifies new PLK2 inhibitors for colorectal cancer treatment using a consensus pharmacological model and validates their effectiveness in cell lines.

## Contribution

A consensus model for PLK2 inhibitor identification is developed, leading to novel compounds with submicromolar potency and high selectivity.

## Key findings

- Two novel PLK2 inhibitors (Y207–5465 and 8012–3246) were identified with submicromolar IC50 values.
- 8012–3246 showed strong cytotoxicity and antiproliferative effects in CRC cell lines.
- 8012–3246 selectively inhibits PLK2 and affects downstream GSK3β phosphorylation.

## 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.