Wedge site story
Nathanael Gray focuses on identifying and blocking genes involved in cancer.
For Nathanael Gray, chemical biology offers a way to discover whether genes thought to be involved in cancer actually play that role and, if so, how they can be stopped. He focuses on a class of proteins known as kinases, which spark interactions between other proteins and are abnormally abundant in many types of cancer cells.
Kinases work by allowing a chemical tag called a phosphate group to be transferred from one protein to another. Each type of kinase — there are more than 500 in the human body — is responsible for transferring phosphates to a specific target protein. Many kinases work in a series and form a molecular signaling network that controls a cell's fate.
To restrain a kinase, scientists would like to use a biochemical "wedge," a small molecule that attaches easily to the kinase's binding site, a tiny pocket on its surface. That would bar the kinase from transferring phosphates to target proteins. Gray and his colleagues are working out the contours and dimensions of binding sites on a specific class of kinases and then testing small molecules whose size and shape is a close match. It's as though the prince in the fairy tale "Cinderella" identified the owner of Cinderella's glass slipper by measuring the slipper's proportions and finding the maiden whose foot corresponded to them.
"Chemical biology involves more than knowing that protein A interacts with protein B," Gray says. "We want to know the exact positions of all the atoms in the protein interaction site. Armed with this knowledge, we can design and test compounds that have the potential to be specific inhibitors and that may become the starting point for future drugs."
Having a set of such molecules will enable researchers to selectively stifle whichever kinase, or group of kinases, they choose, to determine if they contribute to cancer. The "cancer kinases" could then be the target of small molecule-based therapies.
"We've needed a way to dig deeper into the interactions between cell proteins," Gray observes. "Chemical biology lets us explore them at the most basic level."
