Ubiquitin is a protein modifier that regulates many essential cellular processes. The E1 enzyme activates the C-terminal carboxylate of UB to launch its transfer through the E1-E2-E3 cascade onto target proteins to intiate the modification of the protein[2]. CC-220 is a cereblon modulator which achieves greater substrate degradation via tighter binding to the cereblon E3 ligase with IC50 value of 60nM[1]. CC-220, a representative lenalidomide analog, could display significant anti-proliferative and pro-apoptotic activity on sensitive and resistant MM cell lines. In addition, CC-220-stimulated immunomodulatory activity could induce PBMC mediated tumoricidal effect regardless of the level of CRBN expression, leading to greater interleukin-2 secretion and granzyme-b degranulation in immune cells. In vitro, CC-220 exhibited anti-proliferative activity against the MM.1S and Mino cell lines with IC50 values of 13nM and 111.6nM, respectively[3]. Treatment of B cells and T cells with 10nM CC-220 for 24h resulted in a significant decrease in the protein levels of Ikaros and Ailos[4]. In vivo, following oral administration at dosages of 20mg/kg could achieve a Cmax of 2061ng/mL at 0.14h, and had a relative oral bioavailability value of 22.8% in female balb/c mice. Oral administered CC-220 at dosages of 60mg/kg could delay RPMI 8826 tumor growth in the female CB-17 SCID mice[3]. Clinical studies have shown that CC-220 at the dose range of 0.3-6mg in healthy volunteers decreased intracellular Ailos, decreased absolute CD19+ B cells, increased IL-2 and decreased IL-1β production ex vivo[4].
作用机制
CC-220 binds to the protein cereblon, directing the CRL4-CRBN E3 ligase toward the transcription factors Ikaros and Aiolos to cause their ubiquitination and degradation[1].
Iberdomide/伊贝多米德 细胞实验
Cell Line
Concentration
Treated Time
Description
References
CD27-IgD-DN B cells
10 nM
5 days
CC-220 inhibited BAFF- and CD40L-induced plasmablast differentiation and IgG and IgM secretion
J Immunol. 2017 Oct 1;199(7):2388-2407.
CD27+ memory B cells
1, 10, and 100 nM
24 hours
CC-220 significantly reduced Aiolos and Ikaros protein levels and inhibited both BAFF, IL-2, and IL-21–induced and CD40L, IL-2, and IL-21–induced proliferation, plasmablast differentiation, and Ab secretion
J Immunol. 2017 Oct 1;199(7):2388-2407.
H929 cells
10–20 nM
4 months
To study the resistance of H929 cells to Iberdomide
Evaluated antiproliferative and pro-apoptotic activity in combination with bortezomib, showing synergistic effects
Leukemia. 2020 Apr;34(4):1197-1201.
H929/LR cells
0.1 μM
Evaluated antiproliferative activity, showing iberdomide had higher activity than pomalidomide and lenalidomide
Leukemia. 2020 Apr;34(4):1197-1201.
H929 cells
0.1 μM
Evaluated antiproliferative activity, showing iberdomide had higher activity than pomalidomide and lenalidomide
Leukemia. 2020 Apr;34(4):1197-1201.
Primary CD4+ T cells
10 μM
48 hours
Evaluate the effect of Iberdomide on latency reversal, showing significant reversal of latency.
Nucleic Acids Res. 2022 Jun 10;50(10):5577-5598.
B cells from SLE patients
10 nM
5 days
To evaluate the effects of Iberdomide on B cell differentiation into plasmablasts. Results showed that Iberdomide significantly inhibited the differentiation of B cells into plasmablasts and plasma cells and reduced antibody production.
Lupus Sci Med. 2021 Mar;8(1):e000445.
CD19+ B cells from SLE patients
1, 10, 100 nM
5 days
To evaluate the effects of Iberdomide on the activation and differentiation of B cells from SLE patients. Results showed that Iberdomide significantly inhibited TLR7 and IFNα-mediated immunoglobulin production and reduced the number of CD27+CD38+ plasmablasts and CD138+ plasma cells.
Lupus Sci Med. 2021 Mar;8(1):e000445.
Human T cells
10 nM
6 hours
Acute treatment reveals direct effects of IKZF1 degradation, increasing chromatin accessibility
Cell Rep Med. 2024 Nov 19;5(11):101804.
Human T cells
10 nM
14 days
Prevents T cell exhaustion phenotypes, restores tumor cell killing and cytokine secretion
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