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Rational design of CZL-S092: A novel indazole-based PLK4 inhibitor targeting neuroblastoma through virtual screening
Nian Liu1, Ningyuan Hu1, Cunzheng Fan1
1Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China.
Abstract:
Polo like kinase 4 (PLK4) is a critical member of the polo-like kinase family that works as a master regulator of centriole duplication and mitotic progression. Overexpression of PLK4 has been documented in various cancers and PLK4 inhibitors are regarded as a potential strategy for cancer treatment. In this study, we identified indazole derivative 8 as a hit compound through a virtual screening approach. Subsequent fragment-based rational drug design strategy was used to modify the chemical structure of compound 8 and yielded 34 indazole derivatives targeting PLK4. Among them, compound 34b (CZL-S092) exhibited a potent PLK4 inhibitory activity with an IC50 value of 0.9 nM, and exceptional selectivity in a panel of 37 kinases. At the cellular level, compound 34b demonstrated significant antiproliferative activity against the neuroblastoma cell lines IMR-32 and SH-SY5Y with IC50 values of 1.143 μM and 1.329 μM, respectively. Moreover, the colony formation, flow cytometry, wound healing and immunofluorescence analysis further confirmed the in vitro antitumor effects of compound 34b. Meanwhile, compound 34b displayed excellent in vitro drug permeability and plasma protein binding. Furthermore, compound 34b exhibited acceptable in vivo pharmacokinetic properties with the oral bioavailability of 22.1 %. Overall, compound 34b exhibited potent anti-neuroblastoma activities and acceptable pharmacokinetic properties, which served as a favorable lead compound targeting PLK4.
Insights
We identified indazole derivative 34b (CZL-S092) as a potent Polo-like kinase 4 (PLK4) inhibitor. This compound shows significant anti-neuroblastoma activity and favorable pharmacokinetic properties, making it a promising lead for cancer therapy.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Drug Discovery
Background:
- Polo-like kinase 4 (PLK4) is crucial for centriole duplication and mitosis.
- PLK4 overexpression is linked to various cancers, making it a therapeutic target.
- Developing novel PLK4 inhibitors is a key strategy for cancer treatment.
Purpose of the Study:
- To identify and develop novel indazole derivatives as potent PLK4 inhibitors.
- To evaluate the anti-neuroblastoma efficacy and pharmacokinetic profile of lead compounds.
Main Methods:
- Virtual screening identified initial hit compound 8.
- Fragment-based drug design was employed to synthesize 34 indazole derivatives.
- In vitro assays assessed PLK4 inhibition, selectivity, antiproliferative activity, and pharmacokinetics.
Main Results:
- Compound 34b (CZL-S092) demonstrated potent PLK4 inhibition (IC50 = 0.9 nM) with high kinase selectivity.
- Compound 34b exhibited significant antiproliferative effects against neuroblastoma cell lines (IMR-32 and SH-SY5Y).
- In vitro and in vivo studies confirmed 34b's antitumor effects and acceptable pharmacokinetic properties, including 22.1% oral bioavailability.
Conclusions:
- Compound 34b is a potent PLK4 inhibitor with significant anti-neuroblastoma activity.
- The favorable drug-like properties of 34b position it as a promising lead compound for further development in cancer therapy.
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