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Structural Optimization and Anticancer Activity of Polo-like Kinase 1 (Plk1) Polo-Box Domain (PBD) Inhibitors and
Jung-Eun Park1, Hobin Lee1,2, Paola Oliva2
1Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States.
Abstract:
Polo-like kinase 1 (Plk1), a mitotic kinase whose activity is widely upregulated in various human cancers, is considered an attractive target for anticancer drug discovery. Aside from the kinase domain, the C-terminal noncatalytic polo-box domain (PBD), which mediates the interaction with the enzyme's binding targets or substrates, has emerged as an alternative target for developing a new class of inhibitors. Various reported small molecule PBD inhibitors exhibit poor cellular efficacy and/or selectivity. Here, we report structure-activity relationship (SAR) studies on triazoloquinazolinone-derived inhibitors, such as 43 (a 1-thioxo-2,4-dihydrothieno[2,3-e][1,2,4]triazolo[4,3-a]pyrimidin-5(1H)-one) that effectively block Plk1, but not Plk2 and Plk3 PBDs, with improved affinity and drug-like properties. The range of prodrug moieties needed for thiol group masking of the active drugs has been expanded to increase cell permeability and mechanism-based cancer cell (L363 and HeLa) death. For example, a 5-thio-1-methyl-4-nitroimidazolyl prodrug 80, derived from 43, showed an improved cellular potency (GI50 4.1 microM). As expected, 80 effectively blocked Plk1 from localizing to centrosomes and kinetochores and consequently induced potent mitotic block and apoptotic cell death. Another prodrug 78 containing 9-fluorophenyl in place of the thiophene-containing heterocycle in 80 also induced a comparable degree of anti-Plk1 PBD effect. However, orally administered 78 was rapidly converted in the bloodstream to parent drug 15, which was shown be relatively stable toward in vivo oxidation due to its 9-fluorophenyl group in comparison to unsubstituted phenyl. Further derivatization of these inhibitors, particularly to improve the systemic prodrug stability, could lead to a new class of therapeutics against Plk1-addicted cancers.
Insights
Researchers developed novel triazoloquinazolinone inhibitors targeting the polo-box domain of Polo-like kinase 1 (Plk1) for cancer therapy. These compounds show improved potency and selectivity, with prodrugs demonstrating enhanced cell permeability and efficacy in cancer cell death.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- Polo-like kinase 1 (Plk1) is a key mitotic regulator frequently overexpressed in human cancers, making it a promising anticancer target.
- Inhibiting the Plk1 polo-box domain (PBD) offers an alternative strategy to targeting the kinase domain, but existing inhibitors often lack cellular efficacy and selectivity.
- Triazoloquinazolinone derivatives represent a novel scaffold for developing Plk1 PBD inhibitors.
Purpose of the Study:
- To conduct structure-activity relationship (SAR) studies on triazoloquinazolinone-based inhibitors targeting the Plk1 PBD.
- To develop prodrugs with improved cell permeability and anticancer activity.
- To evaluate the in vitro and in vivo efficacy of novel Plk1 PBD inhibitors and their prodrugs.
Main Methods:
- Synthesis and SAR studies of triazoloquinazolinone derivatives.
- Development of prodrug strategies involving thiol group masking.
- In vitro assays to assess Plk1 PBD inhibition, cellular potency (GI50), and effects on mitosis and apoptosis.
- In vivo studies evaluating prodrug conversion and stability.
Main Results:
- Compound 43, a triazoloquinazolinone derivative, selectively inhibited Plk1 PBD with improved affinity and drug-like properties.
- Prodrug 80, derived from 43, demonstrated enhanced cellular potency (GI50 4.1 microM) and effectively induced mitotic block and apoptosis.
- Prodrug 78 showed comparable anti-Plk1 PBD effects, and its parent drug 15 exhibited improved in vivo stability due to a 9-fluorophenyl group.
Conclusions:
- Triazoloquinazolinone-based inhibitors targeting Plk1 PBD are effective anticancer agents with potential for further development.
- Prodrug strategies significantly enhance cellular permeability and efficacy.
- Further optimization of systemic prodrug stability could lead to a new class of therapeutics for Plk1-addicted cancers.
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