Cereblon E3 ubiquitin-ligase

Class

small molecule

Notes

original target text: Cereblon E3 ubiquitin-ligase modulator

Cereblon is a substrate receptor within a multi-subunit ubiquitin ligase complex that normally tags specific proteins for the proteasome, the cell's disposal machinery, marking them for destruction. Certain small molecules, historically classed as immunomodulatory drugs and now including newer cereblon E3 ligase modulators, bind cereblon and change which proteins it recognizes. Rather than blocking cereblon's activity, these molecular-glue compounds redirect it to bind and destroy new target proteins, called neosubstrates, that it would not normally engage. In blood cancers such as multiple myeloma, key neosubstrates are transcription factors that cancer cells depend on for survival; their removal triggers cell death. The same drugs also alter immune cell signaling, enhancing anti-tumor immune responses, which broadens their use beyond direct cancer cell killing. Because a single agent can be engineered to favor particular neosubstrate profiles, chemists have produced successive generations of these modulators seeking greater potency, selectivity, or breadth of protein degradation. This mechanism matters across hematologic malignancies and is being explored in autoimmune disease, since selective degradation of immune transcription factors can also dampen pathological immune activity. It represents one of the clearest examples of targeted protein degradation using small molecules rather than direct enzyme inhibition.