Accelerating molecular glue discovery with a direct-to-biology approach

To find new therapeutics, researchers typically screen large libraries of compounds, which is time-consuming and costly. A study from St. Jude published in the Journal of the American Chemical Society streamlined this process using a “direct-to-biology” approach, which cuts out the middle steps of purifying newly synthesized molecules and instead tests crude mixtures directly against protein targets. 

The researchers, led by Daniel Blair, PhD, Department of Chemical Biology & Therapeutics, used this approach to find promising molecular glues. These compounds work by bringing together two or more biomolecules inside a cell to perform a desired function, such as breaking down a target protein. By capitalizing on a special property of molecular glues — their slower release when bound to the full multiprotein assembly — the team demonstrated that they could efficiently make and find multiple new molecules that promote targeted breakdown of selected proteins. 

“With conventional methods, it would require about two months to analyze what we made. Now, if we go at even a modest pace, we can do that in about 12 hours,” said corresponding author Blair. “That was really impactful for our ability to search through molecules that behave as protein-protein interaction stabilizers.”

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