| 生物活性： |
靶点：CRBN
通路：Ubiquitin
背景说明：Avadomide是一种新型的、多效性通路调节剂,具有抗癌和免疫调节活性,靶向 cereblon (CRBN)。
生物活性：Avadomide (CC 122) is an orally active cereblon modulator. Avadomide modulates cereblon E3 ligase activity and induces apoptosis of diffuse large B-cell lymphoma (DLBCL) cell lines. Avadomide exhibits potent antitumor and immunomodulatory activities[1-2].
In Vitro：Avadomide inhibits proliferation and induces apoptosis in ABC and GCB DLBCL. In DLBCL cell lines，Avadomide-induced degradation or short hairpin RNA-mediated knockdown of Aiolos and Ikaros correlates with increased transcription of IFN-stimulated genes independent of IFN-α，-β，and -γ production and/or secretion and results in apoptosis in both activated B-cell(ABC)and germinal center B-cell DLBCL.[1]
In Vivo：Treatment of female CB-17 SCID mice with Avadomide(CC122)at 3 or 30 mg/kg once daily significantly decreased tumor growth in OCI-LY10 ABC-DLBCL(P = .028 and P < .001，respectively)and WSU-DLCL2 GCB-DLBCL derived xenograft models(P < .01)compared with the vehicle control. In a separate study，we assessed the ability of Avadomide(CC122)to promote degradation of Ikaros and Aiolos in vivo. In the 21-day efficacy study of WSU-DLCL2 xenograft transplanted mice，tumors were excised 1，6，or 24 hours post final dosing. Aiolos and Ikaros expression was interrogated through immunohistochemistry(IHC)and was found to be decreased 64% and 30%，respectively，compared with vehicle within 1 hour of treatment，with a maximal reduction of 94% and 69%，respectively，observed at 6 hours. Aiolos and Ikaros levels partially recovered 24 hours postdosing with protein level within 20% and 34% of vehicle，respectively. The 24-hour postdose Aiolos and Ikaros expression represents the trough compound level following multiple doses of Avadomide(CC122). When the 1-hour time point is compared with the 24-hour postdose time point，there is a significant reduction in Aiolos but not Ikaros expression; however，at the 6-hour time point，both transcription factors are significantly different from the 24-hour time point. Taken together，these data reveal that Avadomide(CC122)inhibited DLBCL tumor growth in vivo and that this activity was associated with the degradation of Aiolos and Ikaros in both ABC- and GCB-DLBCL xenograft models.[1]
细胞实验：将弥漫性巨大B细胞淋巴瘤培养在含10-20% FBS、1% Penicillin/Streptomycin和1 mM sodium pyruvate的RPMI-1640培养基中。然后以2×104细胞/孔的细胞密度将其放置于含DMSP或不同浓度CC-122的培养基。将细胞置于37℃下培养5天，然后将氚化胸腺嘧啶加入到细胞培养基中，孵育6小时。然后收集细胞置于滤板上。待滤板干燥后，加入scintillation fluid，然后在Top-count reader进行读数。[1]
动物实验：Animal Models: CB-17 SCID 小鼠; Dosages: 3或30 mg/kg; Administration: 口服[1]
激酶实验：Female SCID mice(CB17/Icr-Prkdcscid，Charles River)were 8 weeks old，with body weights ranging from 15.0 to 23.2 g，on day 1 of these studies. Each SCID mouse was injected subcutaneously in the right flank with 5x106 OCI-LY10 cells(0.2 ml cell suspension). Tumors were calipered in two dimensions to monitor growth as their mean volume approached 100–150 mm3 . Fourteen days(WSU-DLCL2)or twenty-one days(OCI-LY10)after tumor cell implantation，mice were sorted into treatment groups(n=10/group). Tumors were callipered twice weekly during the study. Avadomide(CC122)was suspended in 0.5% carboxymethyl cellulose: 0.25% Tween-80 in de-ionized water. Vehicle and Avadomide(CC122)were each administered via oral gavage(p.o.)once daily for twenty-eight days(qd x28). [1]
数据来源文献：[1]. Rasco DW， et al. A First-in-Human Study of Novel Cereblon Modulator Avadomide (CC-122) in Advanced Malignancies. Clin Cancer Res. 2019 Jan 1;25(1):90-98.
[2]. Hagner， P.R.et al.CC-122， a pleiotropic pathway modifier， mimics an IFN response and has antitumor activity in DLBCL.Blood.Aug 6;126(6):779-89.
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