Avadomide (CC-122) Avadomide (CC-122), a new chemical entity termed pleiotropic pathway modifier, is a novel agent for Diffuse large B-cell lymphoma(DLBCL) with antitumor and immunomodulatory activity. Its molecular target is the protein cereblon (CRBN), a substrate receptor of the cullin ring E3 ubiquitin ligase complex CRL4 CRBN .
Targets
CRBN
In vitro
CC-122 is a novel agent for DLBCL with antitumor and immunomodulatory activity. In DLBCL cell lines, It binds CRBN and induces degradation or short hairpin RNA-mediated knockdown of Aiolos and Ikaros which correlates with increased transcription of interferon (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 cell lines. CRBN is the molecular target of CC-122, CC-122 binding to CRBN recruits Aiolos/Ikaros to CRL4CRBN, and E3 ligase enzymatic activity is necessary for ubiquitination of Aiolos and Ikaros and thus their proteasomal degradation induced by CC-122. CC-122 induces IFN-regulated proteins and its mediated effects on the IFN pathway is independent of autocrine type I and II IFN secretion and signaling.
In vivo
CC-122 reduces tumor growth in xenograft models established from ABC- and GCB-DLBCL cell lines, and stimulates IL-2 production in primary T cells. Also, in a single-arm CC-122 clinical trial, exposure to CC-122 reduced expression levels of Aiolos and Ikaros in each patient by 25% to 50% demonstrating the utility of these 2 proteins as pharmacodynamic markers of CC-122.
Cell Research(from reference)
Cell lines：DLBCL cell lines(TMD8, U2932, Riva, and OCI-LY10) and GCB-DLBCL lines (Karpas 422, WSU-DLCL2, SUDHL-4, OCI-LY19, and Pfeiffer)
1.Hagner PR, Man HW, Fontanillo C, Wang M, Couto S, Breider M, Bjorklund C, Havens CG, Lu G, Rychak E et al.. (2015) CC-122, a pleiotropic pathway modifier, mimics an interferon response and has antitumor activity in DLBCL.. Blood, 126 (6):(779-89). [PMID:26002965]
2.Rasco DW, Papadopoulos KP, Pourdehnad M, Gandhi AK, Hagner PR, Li Y, Wei X, Chopra R, Hege K, DiMartino J et al.. (2019) A First-in-Human Study of Novel Cereblon Modulator Avadomide (CC-122) in Advanced Malignancies.. Clin Cancer Res, 25 (1):(90-98). [PMID:30201761]
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D2308054