Identification of a New Heterocyclic Scaffold for Inhibitors of the Polo-Box Domain of Polo-like Kinase 1
Celeste N Alverez1,2, Jung-Eun Park1, Kiran S Toti3
1Chemistry Section, Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States.
Abstract:
As a mitotic-specific target widely deregulated in various human cancers, polo-like kinase 1 (Plk1) has been extensively explored for anticancer activity and drug discovery. Although multiple catalytic domain inhibitors were tested in preclinical and clinical studies, their efficacies are limited by dose-limiting cytotoxicity, mainly from off-target cross reactivity. The C-terminal noncatalytic polo-box domain (PBD) of Plk1 has emerged as an attractive target for generating new protein-protein interaction inhibitors. Here, we identified a 1-thioxo-2,4-dihydro-[1,2,4]triazolo[4,3-a]quinazolin-5(1H)-one scaffold that efficiently inhibits Plk1 PBD but not its related Plk2 and Plk3 PBDs. Structure-activity relationship studies led to multiple inhibitors having ≥10-fold higher inhibitory activity than the previously characterized Plk1 PBD-specific phosphopeptide, PLHSpT (Kd ∼ 450 nM). In addition, S-methyl prodrugs effectively inhibited mitotic progression and cell proliferation and their metabolic stability was determined. These data describe a novel class of small-molecule inhibitors that offer a promising avenue for future drug discovery against Plk1-addicted cancers.
Insights
Researchers discovered a new class of small-molecule inhibitors targeting the polo-box domain of polo-like kinase 1 (Plk1). These compounds show promise for developing novel cancer therapies by inhibiting Plk1 in Plk1-addicted cancers.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Cancer Biology
Background:
- Polo-like kinase 1 (Plk1) is a key mitotic regulator frequently deregulated in human cancers.
- Existing Plk1 catalytic domain inhibitors face challenges due to dose-limiting cytotoxicity and off-target effects.
- The Plk1 polo-box domain (PBD) presents a viable target for developing specific protein-protein interaction inhibitors.
Purpose of the Study:
- To identify novel small-molecule inhibitors targeting the Plk1 PBD.
- To develop potent and selective inhibitors against Plk1 PBD for potential anticancer drug discovery.
- To evaluate the efficacy and metabolic stability of newly identified Plk1 PBD inhibitors.
Main Methods:
- Identification of a novel 1-thioxo-2,4-dihydro-[1,2,4]triazolo[4,3-a]quinazolin-5(1H)-one scaffold.
- Structure-activity relationship (SAR) studies to optimize inhibitor potency and selectivity.
- In vitro assays to determine inhibitory activity against Plk1 PBD and related kinases.
- Assessment of S-methyl prodrugs for mitotic progression inhibition, cell proliferation, and metabolic stability.
Main Results:
- A novel scaffold selectively inhibited Plk1 PBD over Plk2 and Plk3 PBDs.
- Optimized inhibitors demonstrated over 10-fold higher potency compared to the PLHSpT phosphopeptide.
- S-methyl prodrugs effectively inhibited cell cycle progression and proliferation.
- Metabolic stability of the prodrugs was evaluated.
Conclusions:
- A novel class of small-molecule Plk1 PBD inhibitors was identified.
- These inhibitors offer a promising alternative to catalytic domain inhibitors for cancer therapy.
- The developed compounds represent a potential new avenue for treating Plk1-dependent cancers.
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