| Size | Price | Stock | Qty |
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| 50mg |
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Purity: ≥98%
| Targets |
Cereblon E3 ligase
Avadomide targets cereblon (CRBN), a substrate receptor for the cullin-4 RING E3 ubiquitin ligase complex. By modulating cereblon E3 ligase activity, it alters the ubiquitination and degradation of specific target proteins, leading to inhibition of the NF-κB pathway and cell cycle arrest at G1 phase. |
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| ln Vitro |
C-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 vitro, Avadomide HCl modulates cereblon E3 ligase activity, inhibits the NF-κB pathway, and arrests the cell cycle at G1 phase. It induces apoptosis in pancreatic cancer cells (PDAC). It mimics an interferon response and has antitumor activity in diffuse large B-cell lymphoma (DLBCL). |
| ln 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
In vivo, Avadomide HCl exhibits potent antitumor activity and immunomodulatory effects. As an orally active compound, it is administered orally in preclinical models. It has shown antitumor activity in DLBCL models through mimicry of interferon signaling and induction of apoptosis. Detailed in vivo protocols are not provided. |
| Enzyme Assay |
CC-122 is a novel agent for DLBCL with antitumor and immunomodulatory activity.CC-122 binds CRBN and degrades Aiolos and Ikaros resulting in a mimicry of IFN signaling and apoptosis in DLBCL. In vitro: CC122 inhibits proliferation and induces apoptosis in ABC and GCB DLBCL. In DLBCL cell lines, CC122-induced degradation or short hairpin RNA-mediated knockdown of Aiolos and Ikaros 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.
Cereblon binding and E3 ligase modulation are assessed using biochemical assays with recombinant cereblon protein and ubiquitination components. The compound's ability to modulate substrate ubiquitination can be measured in cell-free systems using purified E3 ligase complex components and labeled substrate proteins. |
| Cell Assay |
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.
Cell-based assays use cancer cell lines such as PDAC and DLBCL. Cells are treated with Avadomide HCl, and NF-κB pathway inhibition is assessed by measuring downstream signaling. Cell cycle analysis is performed by flow cytometry to confirm G1 arrest. Apoptosis is evaluated by Annexin V staining or caspase activation assays. |
| Animal Protocol |
0.5% carboxymethyl cellulose: 0.25% Tween-80 in deionized water;3 or 30 mg/kg;p.o.
CB-17 SCID mice On the first day of these studies, the female SCID mice (CB17/Icr-Prkdcscid, Charles River) were 8 weeks old and weighed between 15.0 and 23.2 g. Each SCID mouse received a subcutaneous injection of 5x106 OCI-LY10 cells (0.2 ml cell suspension) in the right flank. In order to track growth, tumors were classified in two dimensions as their mean volume got closer to 100–150 mm3. Mice were divided into treatment groups (n=10) after tumor cell implantation, either twenty-one days (OCI-LY10) or fourteen days (WSU-DLCL2). Throughout the study, tumors were called in twice a week.In 0.5% carboxymethyl cellulose:0.25% Tween-80 in de-ionized water, apadomide (CC122) was suspended. For twenty-eight days (qd x28), avadomide (CC122) and the vehicle were each given by oral gavage (p.o.) once daily. [1] In vivo studies would be conducted in mouse xenograft models of DLBCL or PDAC. Avadomide HCl would be administered orally due to its oral bioavailability. Tumor growth inhibition, apoptosis induction, and immune modulation would be assessed. Detailed protocols are not provided in the available references. |
| ADME/Pharmacokinetics |
Pharmacokinetics, Pharmacodynamics and Biomarkers [1]
At all dose levels, arvadomidine plasma concentration-time curves showed a rapid absorption phase and similar median time to peak concentration (Figure 1). After reaching maximum plasma concentration, arvadomidine showed a single-phase decrease at all dose levels. By visual observation of the mean plasma concentration-time curves, plasma exposure of arvadomidine increased in a dose-dependent manner from 0.5 to 3.5 mg. Mild to moderate cumulative plasma exposure of arvadomidine was observed at all seven dose levels after multiple dosings. Supplementary Table S1 summarizes the plasma pharmacokinetic parameters of arvadomidine by date and dose level. Overall, there were inter-patient differences in the area under the concentration-time curve and maximum plasma concentration of arvadomidine, as assessed by percentage of geometric coefficient of variation. The mean total recovery of arvadomidine in urine over 24 hours was 18% to 35% within the 0.5 to 3.5 mg dose range. Within the dose range of 0.5 to 3.5 mg, the mean renal clearance of arvadomimide is 0.53 to 1.31 L/h. The half-life is 7.68 to 27.91 hours. Avadomide HCl has the molecular formula C₁₄H₁₅ClN₄O₃ and a molecular weight of 322.75. It is orally active. The hydrochloride salt form has improved water solubility compared to the free base. Detailed pharmacokinetic parameters are not disclosed. |
| Toxicity/Toxicokinetics |
Most patients (85%) experienced ≥1 treatment-induced adverse event (TEAE) suspected by the investigator to be related to arvadomi. The most common TEAEs (≥15%) across all cohorts were fatigue (44%), neutropenia (29%), and diarrhea (15%). Fourteen patients (41%) experienced ≥Grade 3 arvadomi-related TEAEs. The most common ≥Grade 3 TEAEs were neutropenia (2 in the 1.0 mg group; 1 each in the 1.5 mg, 2.0 mg, 2.5 mg, and 3.5 mg groups; and 3 in the 3.0 mg group) and pneumonia (2 in the 3.0 mg group). Table 2 summarizes the TEAEs in the treatment population. One patient died within 28 days of the last arvadomi dose. One patient with pancreatic cancer died due to disease progression in the 3.5 mg dose group.
No specific toxicity data are detailed in the available references. As a cereblon modulator and immunomodulatory agent, potential toxicities may include hematological effects, immunosuppression, and gastrointestinal disturbances, which are class effects of immunomodulatory drugs. Safety studies would be required for clinical development. |
| References | |
| Additional Infomation |
Avadocimil hydrochloride is the hydrochloride form of avadocimil, a novel small-molecule cereblon modulator with potential antitumor, anti-angiogenic, and immunomodulatory activities. After oral administration, avadocimil binds to and modulates cereblon, promoting the recruitment of hematopoietic transcription factors Aiolos and Ikaros to the Cullin-4 RING E3 ubiquitin ligase complex. This binding leads to ubiquitination of Aiolos and Ikaros, which are then rapidly degraded by the proteasome, simultaneously relieving the inhibition of interferon (IFN)-stimulated genes (including DDX58 and IRF7), ultimately resulting in apoptosis in some tumor cells. Furthermore, the degradation of Aiolos also leads to the de-inhibition of the IL-2 gene, thereby enhancing interleukin-2 production, promoting T lymphocyte co-stimulation, and IL-2-induced T cell proliferation. Avadocimil may also promote the activation of natural killer (NK) cells, thereby enhancing their killing effect on tumor cells. Aiolos and Ikaros are transcriptional repressors known to play important roles in normal B cell and T cell function.
Avadomide HCl (formerly CC-122) is an investigational compound not yet approved for clinical use. It is a novel orally available pleiotropic pathway modulator with potential anticancer and immunomodulatory activity. It has shown antitumor activity in DLBCL by mimicking interferon signaling and inducing apoptosis. |
| Molecular Formula |
C14H14N4O3.HCL
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| Molecular Weight |
322.75
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| Exact Mass |
322.083
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| Elemental Analysis |
C, 52.10; H, 4.68; Cl, 10.98; N, 17.36; O, 14.87
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| CAS # |
1398053-45-6
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| Related CAS # |
1398053-45-6 (HCl);1015474-32-4;
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| PubChem CID |
60199173
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| Appearance |
Solid powder
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
1
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| Heavy Atom Count |
22
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| Complexity |
530
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| Defined Atom Stereocenter Count |
0
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| SMILES |
Cl.O=C1C(CCC(N1)=O)N1C(C2C(=CC=CC=2N=C1C)N)=O
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| InChi Key |
BVJRNKXVSYLNFD-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C14H14N4O3.ClH/c1-7-16-9-4-2-3-8(15)12(9)14(21)18(7)10-5-6-11(19)17-13(10)20;/h2-4,10H,5-6,15H2,1H3,(H,17,19,20);1H
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| Chemical Name |
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione hydrochloride
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| Synonyms |
CC 122 HCl; CC-122; CC122, Avadomide HCl; Avadomide hydrochloride
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.0984 mL | 15.4919 mL | 30.9837 mL | |
| 5 mM | 0.6197 mL | 3.0984 mL | 6.1967 mL | |
| 10 mM | 0.3098 mL | 1.5492 mL | 3.0984 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT03283202 | Completed | Drug: Avadomide (CC-122) Drug: Rituximab |
Diffuse B-Cell Lymphoma Refractory Glioma |
Celgene | October 4, 2017 | Phase 1 |
| NCT03834623 | Completed | Drug: CC-122 Drug: Nivolumab |
Melanoma | H. Lee Moffitt Cancer Center Research Institute |
May 14, 2019 | Phase 2 |
| NCT05688475 | Recruiting | Drug: CC-122 Drug: Dexamethasone |
Non-Hodgkin Lymphoma | Bristol-Myers Squibb | April 11, 2023 | Phase 1 |
| NCT03310619 | Completed | Biological: JCAR017 Drug: Durvalumab Drug: CC-122 |
Lymphoma, Non-Hodgkin Lymphoma, Large B-Cell, Diffuse Lymphoma, Follicular |
Celgene | November 28, 2017 | Phase 1 Phase 2 |
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