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].
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