"Cereblon is part of a protein complex that tags other proteins for destruction. It became infamous because it was targeted by thalidomide, a drug prescribed for morning sickness in the 1950s and 1960s that caused birth defects. Decades later, thalidomide and related compounds were rehabilitated as treatments for blood cancers, precisely because they can redirect cereblon to tag disease‑causing proteins."
"Until now, nearly all of that work focused on cereblon's orthosteric binding site - the same site thalidomide uses. The new study reveals that cereblon also has a second pocket, an allosteric site, that doesn't replace the main binding site but changes what happens once it is engaged."
"That principle is underpinned by a strategy called targeted protein degradation. Chemists design small molecules that bring bad proteins to cereblon, which then marks them for disposal by the cell's disposal machinery."
Cereblon, a protein complex that tags other proteins for destruction, has long been targeted by cancer drugs including thalidomide. Researchers have now identified an allosteric site—a hidden binding pocket—on cereblon in addition to its known orthosteric binding site. This discovery, published in Nature and led by Professor Christina Woo, reveals that cereblon can fine-tune which proteins are destroyed. The allosteric site doesn't replace the main binding site but modifies what occurs when it is engaged. This finding opens new possibilities for targeted protein degradation strategies, potentially enabling chemists to design small molecules that are more selective and safer in directing cereblon to tag disease-causing proteins while avoiding unintended targets.
#cereblon-protein #targeted-protein-degradation #cancer-drug-development #allosteric-binding-sites #drug-selectivity-and-safety
Read at Harvard Gazette
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