Avadomide (CC-122)

Catalog No.S7892 Batch:S789202

Technical Data

Formula	C₁₄H₁₄N₄O₃
Molecular Weight	286.29	CAS No.	1015474-32-4
Solubility (25°C)*	In vitro	DMSO	57 mg/mL (199.09 mM)
		Water	Insoluble
		Ethanol	Insoluble
* <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations. * Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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Biological Activity

Description

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 ^[1]

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 CRL4^CRBN, 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^[1].

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^[1].

Protocol (from reference)

Cell Assay:^{^[1]}	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) Concentrations 0.01 to 10 000 nM Incubation Time 5 days Method Diffuse Large B-Cell Lymphoma are cultured in RPMI-1640 containing 10-20% fetal bovine serum, 1% Penicillin/Streptomycin and 1 mM sodium pyruvate. 2×10⁴ cells are plated per well in media containing either DMSO or various concentrations of CC-122. Cells are cultured for 5 days at 37 degrees Celsius after which tritiated thymidine is added to the cell culture for the final 6 hours. Cells are subsequently harvested onto filter plates. After the plates have dried, scintillation fluid is added to the plates and read on a Top-count reader
Animal Study:^{^[1]}	Animal Models CB-17 SCID mice Dosages 3 or 30 mg/kg Administration p.o.

Cell Assay:^{^[1]}

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)
Concentrations
0.01 to 10 000 nM
Incubation Time
5 days
Method
Diffuse Large B-Cell Lymphoma are cultured in RPMI-1640 containing 10-20% fetal bovine serum, 1% Penicillin/Streptomycin and 1 mM sodium pyruvate. 2×10⁴ cells are plated per well in media containing either DMSO or various concentrations of CC-122. Cells are cultured for 5 days at 37 degrees Celsius after which tritiated thymidine is added to the cell culture for the final 6 hours. Cells are subsequently harvested onto filter plates. After the plates have dried, scintillation fluid is added to the plates and read on a Top-count reader

Animal Study:^{^[1]}

Animal Models
CB-17 SCID mice
Dosages
3 or 30 mg/kg
Administration
p.o.

References

[1] Hagner PR, et al. Blood. 2015, 126(6):779-89.

Selleck's Avadomide (CC-122) has been cited by 5 publications

Degradome analysis to identify direct protein substrates of small-molecule degraders [ bioRxiv, 2024, 10.1101/2024.01.28.577572]	PubMed: none
Lenalidomide bypasses CD28 co-stimulation to reinstate PD-1 immunotherapy by activating Notch signaling [ Cell Chem Biol, 2022, S2451-9456(22)00204-5]	PubMed: 35732177
IRF4 modulates the response to BCR activation in chronic lymphocytic leukemia regulating IKAROS and SYK [ Leukemia, 2021, 35(5):1330-1343]	PubMed: 33623139
A Cereblon Modulator CC-885 Induces CRBN- and p97-Dependent PLK1 Degradation and Synergizes with Volasertib to Suppress Lung Cancer [ Mol Ther Oncolytics, 2020, 18:215-225]	PubMed: 32728610
Genome-wide CRISPR screens reveal genetic mediators of cereblon modulator toxicity in primary effusion lymphoma. [ Blood Adv, 2019, 3(14):2105-2117]	PubMed: 31300418

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SHIPPING AND STORAGE
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