First metabolically activated molecular glue degrader may target cancer cells under oxidative stress
Investigators at Dana-Farber Cancer Institute have developed a platform for systematically discovering molecular glues that could become protein degradation drug candidates. The platform could help drug developers dramatically expand the range of disease-related proteins that can be therapeutically targeted for elimination via protein degradation.
Investigators at Dana-Farber Cancer Institute have discovered a groundbreaking platform for systematically discovering molecular glue degraders, potentially revolutionizing cancer treatment. The platform enabled the team to identify the first metabolically activated molecular glue degrader, suggesting that molecular glues may be more context-dependent and tunable than previously thought.
This discovery could dramatically expand the range of disease-related proteins that can be targeted for elimination via protein degradation, offering a new approach to fighting cancer and other diseases. The team tested their system by screening seven E3 ligases and discovered that a protein called DDX18 was attracted to the understudied E3 ligase DCAF11.
They identified a molecule called M12 as a potential molecular glue degrader, but its activity only occurred under specific metabolic conditions found more frequently in cancer cells than normal cells. This discovery opens up new possibilities for targeting cancer-related proteins using a more context-dependent and potentially tunable approach.
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