CC-122, also known as avadomide, binds to CRBN and induces degradation of aiolos and ikaros that result in cell apoptosis. It is a antitumor and immunomodulatory agent used to treat DLBCL.
Cereblon (CRBN) is a substrate receptor of the Cullin 4 RING E3 ubiquitin ligase complex, that promotes the ubiquitination and subsequent degradation of 2 common substrates, transcription factors Alolos and Ikaros. CC-122 is a new chemical entity termed pleiotropic pathway modifier, binds CRBN and induces apoptosis in a broad panel of diffuse large B-cell lymphoma (DLBCL), and stimulated IL-2 production in primary T cells. In vitro, CC-122 induced growth arrest and apoptosis in activated B-cell and germinal center B-cell DLBCL cell lines at concentration ranging in 0.1 – 10 μM. Treatment with 10 μM CC-122 promoted CRBN-Ikaros interaction and subsequent proteasomal degradation of Aiolos and Ikaros in DLBCL cell lines TMD8, OCI-LY10 and Karpase 422[3]. Treatment with 1 μM CC-122 inhibited cell invasion and migration in hepatocellular carcinoma (HCC) cell lines. In addition, CC-122 significantly reduced TCG-4 J and its target genes SPP1, AXIN2, MMP7, ASPH, CD24, ANXA1, and CAMK2N1[4]. In vivo, treatment with 30 mg/kg once daily for 30 days significantly decreased tumor growth in OCILY10 ABC-DLBCL and WSU-DLCL2 derived xenograft models. Administration of CC-122 at 30 mg/kg once daily for 24h significantly decreased Aiols and IKaros expression in WSU-DLCL2 xenograft transplanted mice[3]. Oral administration of CC-122 at 30 mg/kg for 40 days reduced growth rate of HAK-1A-J tumors in HCC xenografts model[4]. A phase I Clinical trial study shows that CC-122 might regulate the NK phenotype and its activity due to the reduced accumulation of myeloid derived suppressor cell and eventually decrease the Tregs subsets[5].
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