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].
Avadomide 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Hep3B cells
1 μmol/L or 10 μmol/L
12 or 24 hours
To identify novel targets of avadomide, and found decreased ZMYM2 protein level
To assess the effect of Avadomide on the degradation of Aiolos and Ikaros and the expression of ISGs (e.g., IRF7), results showed that Avadomide significantly increased IRF7 protein expression in sensitive cells.
Clin Cancer Res. 2022 Aug 2;28(15):3367-3377.
Avadomide 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
BALB/c mice
ZMYM2–FGFR1-transformed Ba/F3 leukemia model
Oral gavage
50 mg/kg
Twice daily for 7 days
To evaluate the in vivo antiproliferative effect of avadomide on ZMYM2–FGFR1-dependent leukemia cells, showing significant reduction in tumor burden
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