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A novel anti-tumor inhibitor identified by virtual screen with PLK1 structure and zebrafish assay
Jing Lu1, Shengchang Xin, Huan Meng
1Shenzhen Graduate School of Peking University, Shenzhen, China.
Abstract:
Polo-like kinase 1 (PLK1), one of the key regulators of mitosis, is a target for cancer therapy due to its abnormally high activity in several tumors. Plk1 is highly conserved and shares a nearly identical 3-D structure between zebrafish and humans. The initial 10 mitoses of zebrafish embryonic cleavages occur every∼30 minutes, and therefore provide a rapid assay to evaluate mitosis inhibitors including those targeting Plk1. To increase efficiency and specificity, we first performed a computational virtual screen of∼60000 compounds against the human Plk1 3-D structure docked to both its kinase and Polo box domain. 370 candidates with the top free-energy scores were subjected to zebrafish assay and 3 were shown to inhibit cell division. Compared to general screen for compounds inhibiting zebrafish embryonic cleavage, computation increased the efficiency by 11 folds. One of the 3 compounds, named I2, was further demonstrated to effectively inhibit multiple tumor cell proliferation in vitro and PC3 prostate cancer growth in Xenograft mouse model in vivo. Furthermore, I2 inhibited Plk1 enzyme activity in a dose dependent manner. The IC50 values of I2 in these assays are compatible to those of ON-01910, a Plk1 inhibitor currently in Phase III clinic trials. Our studies demonstrate that zebrafish assays coupled with computational screening significantly improves the efficiency of identifying specific regulators of biological targets. The PLK1 inhibitor I2, and its analogs, may have potential in cancer therapeutics.
Insights
Computational screening and zebrafish assays efficiently identified I2, a novel Polo-like kinase 1 (PLK1) inhibitor. This compound shows promise for cancer therapy by inhibiting tumor cell proliferation and prostate cancer growth.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Polo-like kinase 1 (PLK1) is a key regulator of mitosis and a validated cancer target due to its overexpression in various tumors.
- PLK1 exhibits high structural conservation between humans and zebrafish, making zebrafish a suitable model for drug screening.
- Rapid zebrafish embryonic cell divisions offer a high-throughput assay for evaluating mitosis inhibitors.
Purpose of the Study:
- To develop an efficient and specific screening method for identifying novel PLK1 inhibitors.
- To validate the identified inhibitors in vitro and in vivo cancer models.
- To assess the therapeutic potential of a lead compound targeting PLK1.
Main Methods:
- Computational virtual screening of ~60,000 compounds against human PLK1 kinase and Polo box domains.
- Zebrafish embryonic cleavage assay to evaluate mitosis inhibition.
- In vitro proliferation assays and in vivo Xenograft mouse models for tumor growth inhibition.
- Enzyme activity assays to determine IC50 values.
Main Results:
- Computational screening identified 370 candidates, with 3 inhibiting zebrafish cell division, increasing efficiency 11-fold over general screens.
- One compound, I2, demonstrated significant inhibition of multiple tumor cell proliferation in vitro and PC3 prostate cancer growth in vivo.
- I2 dose-dependently inhibited PLK1 enzyme activity, with IC50 values comparable to the clinical-stage inhibitor ON-01910.
Conclusions:
- The combination of computational screening and zebrafish assays significantly enhances the efficiency of identifying specific biological target regulators.
- The novel PLK1 inhibitor I2 and its analogs show potential as effective cancer therapeutics.
