生物活性

• 描述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 C^max 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].
• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT00002431	Candidiasis, Oral ... more >> HIV Infections Collapse <<	Not Applicable	Completed	-	United States, California ... more >> Dental Research Institute / UCLA Med Ctr Los Angeles, California, United States, 900951762 UCSF / Stomatology Clinical Ctr San Francisco, California, United States, 94143 United States, Ohio Ohio State Univ Hosp Clinic Columbus, Ohio, United States, 432101228 United States, Texas Bering Dental Clinic Houston, Texas, United States, 77006 Hermann Hosp / Univ Texas Health Science Ctr Houston, Texas, United States, 77030 Collapse <<
  NCT02034773	Healthy Volunteers	Phase 1	Completed	-	United States, Wisconsin ... more >> Covance Clinical Research Unit Madison, Wisconsin, United States, 53704 Collapse <<
  NCT00530751	-	-	Withdrawn(PI left)	-	United States, Ohio ... more >> Mercy Cancer Center at Mercy Medical Center Canton, Ohio, United States, 44708 Geauga Regional Hospital Chardonr, Ohio, United States, 44024 Lake/University Ireland Cancer Center Mentor, Ohio, United States, 44060 Southwest General Health Center Middleburgh Heights, Ohio, United States, 44130 UHHS Chagrin Highlands Medical Center Orange Villager, Ohio, United States, 44122 University Suburban Health Center South Euclid, Ohio, United States, 44121 UHHS Westlake Medical Center Westlaker, Ohio, United States, 44145 Collapse <<

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• 参考文献

• [1] Matyskiela M, Zhang W, Man H, et al. A Cereblon Modulator (CC-220) with Improved Degradation of Ikaros and Aiolos. Journal of Medicinal Chemistry, 2017, 61(2): 535-542

  [2] Zhao B, Bhuripanyo K, Schneider J R, et al. Specificity of the E1-E2-E3 enzymatic cascade for ubiquitin C-terminal sequences identified by phage display. ACS Chemical Biology, 2012, 7(12): 2027-2035

  [3] Xiao D, Wang Y, Hu X, et al. Design, synthesis and biological evaluation of the thioether-containing lenalidomide analogs with anti-proliferative activities. European Journal of Medicinal Chemistry, 2019: 419-430

  [4] Schafer P H, Ye Y, Wu L, et al. Cereblon modulator iberdomide induces degradation of the transcription factors Ikaros and Aiolos: immunomodulation in healthy volunteers and relevance to systemic lupus erythematosus. Annals of the Rheumatic Diseases, 2018, 77(10): 1516-1523.