Original story from the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences (Vienna, Austria). The mechanism by which a small molecule can use two distinct pathways for degrading its target protein has been identified, offering insight into how we can make targeted protein degraders more effective. Most drugs work by inhibition: they block a protein’s activity but leave the protein itself intact. Targeted protein degradation takes a fundamentally different approach, harnessing the cell’s own quality-control machinery to remove proteins entirely. To do this, degrader molecules bring a target protein into proximity with an E3 ligase, an enzyme complex that labels proteins for destruction by the proteasome. This strategy has transformed drug discovery, particularly because it allows researchers to tackle proteins that are difficult to inhibit directly and to eliminate not only their enzymatic activity but also their structural functions. A new layer of control in protein degradation Until now, however, most degraders have relied on a single ligase. This creates a vulnerability: if cells lose or alter that pathway, for example through mutation or adaptation in cancer, the drug can become ineffective. Overcoming this limitation has been a central challenge in the field. In their new study, researchers from Georg Winter’s Group at CeMM Research Center for Molecular Medicine and AITHYRA (both Institutes of the Austrian Academy of Sciences, Vienna, Austria), together with Alessio Ciulli’s group at the Centre for Targeted Protein Degradation (CeTPD; Dundee, UK), investigated a small molecule designed to degrade SMARCA2/4, the central…
