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Beyond PROTACs and the proteasome: broadening the TAC toolbox

Interest is growing in applying the logic of PROTACs to direct more types of molecules to more types of target

The idea of sending disease-driving proteins to the cell’s garbage can is only the first act in a field that now centers around targeted degradation. In the sequel, researchers are extending the principle to other types of cellular machinery, with iterations that promise access to an even broader range of targets, and to enzyme functions beyond protein degradation.

These next-generation targeting chimeras, or “TACs,” are opening the door to therapies that activate, deactivate or protect targets of interest. But the first translational challenges are likely to be getting the right bioavailability and kinetics.

At least seven companies have launched in the last eight years to develop therapeutics based on targeted protein degraders -- a class of molecules introduced in the early 2000s by Yale University’s Craig Crews, who dubbed them PROTACs (proteolytic targeting chimeras). The approach offers a way to block the activity of intracellular proteins whose structure, localization or resistance mutations make them difficult to target by conventional small molecules or mAbs.

Each of these companies is following a similar blueprint: bind a protein of interest and bring it to a ubiquitin ligase, which then tags it for degradation

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