Related Experiment Video
Updated: Oct 3, 2025
Author Spotlight: Advancing Structural and Biochemical Studies of Proteins Through Thermal Shift Assays
Published on: August 9, 2024
Novel Aurora A and Protein Kinase C (α, β1, β2, and θ) Multitarget Inhibitors: Impact of Selenium Atoms on the
Krikor Bijian1, Dominik Wernic1, Anita K Nivedha2,3
1Segal Cancer Centre and Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Departments of Medicine and Oncology, McGill University, Montreal, Quebec H3A 0B8, Canada.
Abstract:
Aurora kinases and protein kinase C (PKC) have been shown to be involved in different aspects of cancer progression. To date, no dual Aurora/PKC inhibitor with clinical efficacy and low toxicity is available. Here, we report the identification of compound 2e as a potent small molecule capable of selectively inhibiting Aurora A kinase and PKC isoforms α, β1, β2 and θ. Compound 2e demonstrated significant inhibition of the colony forming ability of metastatic breast cancer cells in vitro and metastasis development in vivo. In vitro kinase screening and molecular modeling studies revealed the critical role of the selenium-containing side chains within 2e, where selenium atoms were shown to significantly improve its selectivity and potency by forming additional interactions and modulating the protein dynamics. In comparison to other H-bonding heteroatoms such as sulfur, our studies suggested that these selenium atoms also confer more favorable PK properties.
Insights
A novel compound selectively inhibits Aurora A kinase and protein kinase C (PKC) isoforms, showing potential against metastatic breast cancer by improving drug properties through selenium atoms.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Aurora kinases and protein kinase C (PKC) are implicated in cancer progression.
- Existing dual Aurora/PKC inhibitors lack clinical efficacy and exhibit toxicity.
Purpose of the Study:
- To identify a novel dual inhibitor of Aurora A kinase and PKC isoforms.
- To evaluate the anti-cancer efficacy and mechanism of action of the identified compound.
Main Methods:
- Small molecule screening and synthesis.
- In vitro kinase assays and cell-based assays (colony formation).
- In vivo metastasis models and molecular modeling.
Main Results:
- Compound 2e selectively inhibits Aurora A kinase and PKC isoforms (α, β1, β2, θ).
- Compound 2e inhibits metastatic breast cancer cell growth in vitro and metastasis in vivo.
- Selenium-containing side chains enhance compound 2e's potency, selectivity, and pharmacokinetic properties.
Conclusions:
- Compound 2e represents a promising therapeutic candidate for metastatic breast cancer.
- The unique role of selenium in drug design is highlighted for improved efficacy and PK properties.
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
01:16Adrenergic Agonists: Chemistry and Structure-Activity Relationship
Aromatic ring substitutions: Substituting the aromatic ring with –OH groups at positions 3 and 4 yields catecholamines (e.g., epinephrine), which have a high affinity for adrenoceptors. Hydrogen bonding between –OH groups and receptors enhances adrenergic activity.
Separation of...
02:54Protein Kinases and Phosphatases
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
01:28Structure-Activity Relationships and Drug Design
SAR studies the intricate relationship between a drug's chemical structure and biological activity. It focuses on understanding how modifications to a drug's structure can influence...
02:34Inhibition of Cdk Activity
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...