The ubiquitin proteasome system plays an essential role in maintaining cellular homeostasis. It regulates the timely degradation of diverse cellular proteins, including cell-cycle regulatory proteins, transcription factors, oncoproteins, and tumor suppressors.1-3 Abnormal regulation of E3 ubiquitin ligases, the largest family of ubiquitin ligases, may contribute to uncontrolled proliferation, genomic instability, and cancer.4,5
Cereblon (CRBN) is a component of an E3 ubiquitin ligase complex (CRL4CRBN) that includes Cul4, DDB1, and Roc1.6-10 CRBN is the protein target of the immunomodulatory agents lenalidomide and pomalidomide as well as the pleiotropic pathway modifier (PPMTM) CC-122.6-12 Binding of immunomodulatory or PPM agents to CRBN is hypothesized to result in altered ubiquitination and degradation of key substrates, including Aiolos and Ikaros, inducing T-cell activation via interleukin-2 upregulation and direct anti-tumor effects through interferon regulatory factor 4 and myc downregulation, as shown in preclinical studies.7-9,13
Proposed Mechanism of Action in Hematologic Malignancies
Proposed Mechanism of Action in Solid Tumors
The safety and efficacy of the agents and/or uses under investigation have not been established. There is no guarantee that the agents will receive health authority approval or become commercially available in any country for the uses being investigated.