Selective Proteolysis to Study the Global Conformation and Regulatory Mechanisms of c-Src Kinase.

Protein kinase pathways are traditionally mapped by monitoring downstream phosphorylation. Meanwhile, the noncatalytic functions of protein kinases remain under-appreciated as critical components of kinase signaling. c-Src is a protein kinase known to have noncatalytic signaling function important in healthy and disease cell signaling.

Development of a chimeric c-Src kinase and HDAC inhibitor.

On the basis of synergism observed between a selective c-Src kinase inhibitor with an HDAC inhibitor, the development of the first chimeric c-Src kinase and HDAC inhibitor is described. The optimized chimeric inhibitor is shown to be a potent c-Src and HDAC inhibitor. Chimeric inhibitor is further shown to be highly efficacious in cancer cell lines and significantly more efficacious than a dual-targeting strategy using discrete c-Src and HDAC inhibitors.

Activation state-selective kinase inhibitor assay based on ion mobility-mass spectrometry.

The discovery of activation state dependent kinase inhibitors, which bind specifically to the inactive conformation of the protein, is considered to be a promising pathway to improved cancer treatments. Identifying such inhibitors is challenging, however, because they can have Kd values similar to molecules known to inhibit kinase function by interacting with the active form. Further, while inhibitor induced changes within the kinase tertiary structure are significant, few technologies are able to correctly assign inhibitor binding modes in a high-throughput fashion based exclusively on protein-inhibitor complex formation and changes in local protein structure.

Recent Development of Bifunctional Small Molecules to Study Metal-Amyloid-β Species in Alzheimer's Disease.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease related to the deposition of aggregated amyloid-β (Aβ) peptides in the brain. It has been proposed that metal ion dyshomeostasis and miscompartmentalization contribute to AD progression, especially as metal ions (e.g.