October 7, 2025
Cereblon E3 ligase modulators (CELMoDs) are a type of small molecule therapeutic modality in clinical development for the treatment of multiple myeloma. Specifically, CELMoDs are “molecular glues.” Although similar to PROTACs, molecular glues differ in their structure and mechanism of action.
CELMoDs do not target and kill myeloma cells directly; their mechanism of action is more indirect. CELMoDs target cereblon, a protein in the human body that can form a protein complex with other proteins (DDB1, Cul4, and Rbx1) to create an E3 ligase (CRL4-cereblon). E3 ligases are involved in the Ubiquitin-Proteasome Pathway (UPP) which degrades proteins in the human body. E1, E2, and E3 proteins work in concert to tag a protein with ubiquitin. Once a protein is tagged with ubiquitin, it is marked for destruction by a proteasome.
CELMoDs bind to cereblon to make it more likely to bind to certain proteins. The binding to cereblon modulates the function of the CRL4-cereblon E3 ligase, which in turns degrades certain transcription factors such as ikaros and aiolos. These transcription factors are over-expressed in multiple myeloma, and are needed for the cancer to proliferate. So, by degrading the ikaros and aiolos transcription factors, the cancer cells are unable to proliferate and multiple myeloma is treated.
CELMoDs are similar to IMiDs (immunomodulatory imide drugs), such as thalidomide, lenalidomide, and pomalidomide. IMiDs also bind cereblon to increase cereblon’s affinity for the ikaros and aiolos transcription factors. Looking forward, Iberdomide (CC-220) and mezigdomide (CC92480) are two CELMoDs to watch as they progress through the clinic.
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