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Purity: ≥98%
Avadomide (formerly known as CC-122) is a novel, orally available pleiotropic pathway modulator with potential with anticancer and immunomodulatory activity. It targets the protein cereblon (CRBN), a substrate receptor of the cullin ring E3 ubiquitin ligase complex CRL4CRBN. Avadomide mimics an interferon response and has antitumor activity in DLBCL (Diffuse large B-cell lymphoma). Avadomide binds CRBN and promotes the degradation of Aiolos and Ikaros resulting in a mimicry of IFN signaling and apoptosis in DLBCL. As a new chemical entity and a pleiotropic pathway modifier, Avadomide has potential application in the treatment of cancer and immune disease.
| Targets |
Cereblon E3 ligase
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|---|---|
| ln Vitro |
In ABC and GCB DLBCL, avadomide suppresses proliferation and triggers apoptosis. Aiolos and Ikaros can be degraded by avadomide or knocked down using short hairpin RNA. This leads to apoptosis in both activated B-cell (ABC) and germinal center B-cell DLBCL cell lines and increases transcription of IFN-stimulated genes regardless of IFN-α, -β, and -γ production and/or secretion.[1]
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| ln Vivo |
When Avadomide (CC122) was administered once daily at 3 or 30 mg/kg to female CB-17 SCID mice, the tumor growth in OCI-LY10 ABC-DLBCL and WSU-DLCL2 GCB-DLBCL derived xenograft models was significantly reduced (P <.01) in comparison to the vehicle control. We evaluated avadomide (CC122)'scapacityto encourage Ikaros and Aiolos degradation in vivo in a different investigation. The WSU-DLCL2 xenograft transplanted mice used in the 21-day efficacy study had tumors removed 1, 6, or 24 hours after the last dose.Using immunohistochemistry (IHC), the expression of Aiolos and Ikaros was examined. Within the first hour of treatment, there was a reduction of 64% and 30%, respectively, compared with the vehicle; at 6 hours, there was a maximal reduction of 94% and 69%, respectively. Twenty-four hours after dosing, Aiolos and Ikaros levels showed partial recovery, with protein levels at 20% and 34% of vehicle, respectively. The trough compound level after several doses of avadomide is represented by the 24-hour postdose Aiolos and Ikaros expression (CC122).Aiolos expression is significantly lower at the 1-hour time point compared to the 24-hour postdose time point, but not Ikaros expression. Both transcription factors, however, are significantly different at the 6-hour time point compared to the 24-hour time point. Together, these findings show that avadomide (CC122) inhibited the growth of DLBCL tumors in vivo and that this activity was connected to the GCB- and ABC-DLBCL xenograft models' degradation of Ikaros and Aiolos.[1]
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| Cell Assay |
CC-122 inhibits proliferation and induces apoptosis in ABC and GCB DLBCL[1]
To explore the antiproliferative activity of CC-122 in DLBCL cell lines, thymidine incorporation assays were performed in a panel of DLBCL cell lines after 5 days of treatment with CC-122. Exposure of 4 ABC-DLBCL lines (TMD8, U2932, Riva, and OCI-LY10) and 5 GCB-DLBCL lines (Karpas 422, WSU-DLCL2, SUDHL-4, OCI-LY19, and Pfeiffer) cell lines with 0.01 to 10 000 nM CC-122 for 5 days led to a marked decrease in proliferation (Figure 1A). The ABC cell lines were more sensitive than the GCB cell lines (ABC 50% inhibition concentration range, 8 nM to 6 μM; GCB 50% inhibition concentration range, 1 μM to >10 μM). CC-122 promotes CRBN-Ikaros interaction and subsequent proteasomal degradation of Aiolos and Ikaros in vitro[1] The thalidomide binding domain of CRBN was recently shown to contain a hydrophobic pocket in which 3 tryptophan residues govern the binding with the glutarimide moiety within thalidomide, lenalidomide, and pomalidomide.9 As the chemical structure of CC-122 contains a glutarimide ring, we explored if CC-122 binds CRBN. As shown in Figure 2A, CRBN from U266 multiple myeloma cell extracts interacted with FG affinity beads coupled to an immobilized thalidomide analog (DMSO control lane). Furthermore, incubation of the complex with increasing concentration of free CC-122 resulted in the displacement of CRBN from the thalidomide analog–immobilized beads, consistent with CC-122 competing with thalidomide for binding CRBN. Additionally, fluorescence quenching studies on a purified C terminus fragment of CRBN (amino acids 321-440) confirmed direct binding of CC-122 with CRBN (supplemental Figure 1). |
| Animal Protocol |
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]
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| ADME/Pharmacokinetics |
Pharmacokinetics, pharmacodynamics, and biomarkers[1]
At all dose levels, the avadomide plasma concentration versus time profiles were characterized by a rapid absorption phase and similar median time to maximum concentration (Fig. 1). After attainment of maximum observed concentration in plasma, avadomide appeared to decrease in a monophasic manner at all dose levels. By visual inspection of mean plasma concentrations versus time profiles, avadomide plasma exposures increased in a dose-dependent manner across the 0.5- to 3.5-mg dose range. All 7 dose levels showed mild-to-moderate accumulation of avadomide plasma exposure after multiple doses. Supplementary Table S1 summarizes avadomide plasma pharmacokinetic parameters by day and dose level. In general, as assessed from the geometric coefficient of variation percentage, interpatient variability was noted for both avadomide area under the concentration–time curve and maximum observed concentration in plasma. The mean total recovery of avadomide in urine within 24 hours ranged from 18% to 35% across the 0.5- to 3.5-mg dose range. The mean avadomide renal clearance ranged from 0.53 to 1.31 L/h across the 0.5- to 3.5-mg dose range. The t1/2 ranged from 7.68 to 27.91 hours. |
| Toxicity/Toxicokinetics |
Most patients (85%) had ≥1 TEAE that was suspected by the investigators of being related to avadomide. Across all cohorts, the most common TEAEs (≥15%) were fatigue (44%), neutropenia (29%), and diarrhea (15%). Avadomide-related grade ≥3 TEAEs occurred in 14 patients (41%). The most common grade ≥3 TEAEs were neutropenia (2 patients in the 1.0-mg cohort; 1 patient each in the 1.5-, 2.0-, 2.5-, and 3.5-mg cohorts; and 3 patients in the 3.0-mg cohort) and pneumonia (2 patients in the 3.0-mg cohort). Table 2 summarizes the TEAEs in the treated population. One death occurred within 28 days of the last dose of avadomide; 1 patient with pancreatic carcinoma in the 3.5-mg cohort died due to disease progression.
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| References | |
| Additional Infomation |
Avadomide is under investigation in clinical trial NCT02031419 (Novel Combinations of CC-122, CC-223, CC-292, and Rituximab in Diffuse Large B-cell Lymphoma and Follicular Lymphoma).
Avadomide is a novel, small molecule cereblon-modulating agent with potential antineoplastic, antiangiogenic and immunomodulatory activities. Upon oral administration, avadomide binds to and modulates cereblon to promote recruitment of the hematopoietic transcription factors Aiolos and Ikaros to the Cullin-4 RING E3 ubiquitin ligase complex. This binding results in the ubiquitination and rapid proteasomal degradation of Aiolos and Ikaros and the derepression of interferon (IFN)-stimulated genes, including DDX58 and IRF7, leading to apoptosis of certain tumor cells. Additionally, Aiolos degredation leads to derepression of the IL2 gene, thereby enhancing interleukin-2 production, costimulation of T-lymphocytes and IL-2-induced T-cell proliferation. Avadomide may also promote the activation of natural killer (NK) cells, potentially enhancing tumor cell killing. Aiolos and Ikaros are transcriptional repressors known to play an important role in normal B- and T-cell function. Drug Indication Treatment of mature B-cell neoplasms |
| Molecular Formula |
C14H14N4O3
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|---|---|
| Molecular Weight |
286.29
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| Exact Mass |
286.107
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| Elemental Analysis |
C, 58.74; H, 4.93; N, 19.57; O, 16.77
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| CAS # |
1015474-32-4
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| Related CAS # |
(S)-Avadomide-d1;1620055-10-8
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| PubChem CID |
24967599
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| Appearance |
White to gray solid powder
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| LogP |
1.174
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
1
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| Heavy Atom Count |
21
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| Complexity |
530
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C1C([H])(C([H])([H])C([H])([H])C(N1[H])=O)N1C(C2=C(C([H])=C([H])C([H])=C2N=C1C([H])([H])[H])N([H])[H])=O
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| InChi Key |
RSNPAKAFCAAMBH-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C14H14N4O3/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)
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| Chemical Name |
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione
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| Synonyms |
Avadomide; CC 122; CC-122; 1015474-32-4; 3-(5-Amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione; Avadomide [USAN]; Avadomide(CC-122); CC 122; CC122
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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) |
DMSO : 33.33~57 mg/mL ( 116.42~199.09 mM )
Ethanol : ~1 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (8.73 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 + to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.4930 mL | 17.4648 mL | 34.9296 mL | |
| 5 mM | 0.6986 mL | 3.4930 mL | 6.9859 mL | |
| 10 mM | 0.3493 mL | 1.7465 mL | 3.4930 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 | 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 |
| 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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