Novel Aurora A and Protein Kinase C (α, β1, β2, and θ) Multitarget Inhibitors: Impact of Selenium Atoms on the Potency and Selectivity
Krikor Bijian, Dominik Wernic, Anita K. Nivedha, Jie Su, Felicia Phei Lin Lim, Caitlin E. Miron, Hind Amzil, Nicolas Moitessier, Moulay A. Alaoui‐Jamali
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.