Publications by authors named "Phillip J Day"
The DDR1 and DDR2 receptor tyrosine kinases are activated by extracellular collagen and have been implicated in a number of human diseases including cancer. We performed a fragment-based screen against DDR1 and identified fragments that bound either at the hinge or in the back pocket associated with the DFG-out conformation of the kinase. Modeling based on crystal structures of potent kinase inhibitors facilitated the "back-to-front" design of potent DDR1/2 inhibitors that incorporated one of the DFG-out fragments.
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- A new Type II kinase inhibitor has been developed specifically for maternal embryonic leucine zipper kinase (MELK) using a method known as structure-based ligand design.
- This approach involved detailed structural analysis of the protein-ligand interactions through techniques like X-ray crystallography, which helped identify a unique pocket for the inhibitor to bind.
- The optimized inhibitor is highly effective, operating at low nanomolar concentrations and able to easily enter cells, making it a promising tool for researching MELK's biological functions.
Article Synopsis
- Fragment-based drug design was used effectively to target maternal embryonic leucine zipper kinase (MELK).
- Researchers identified an initial low-affinity fragment that bound to MELK's hinge region in a unique way.
- This fragment was then optimized into a potent, cell-penetrating inhibitor with low nanomolar affinity, making it a valuable tool for studying MELK's biological roles.