Iberdomide targets cereblon (CRBN), a component of the CRL4^CRBN E3 ubiquitin ligase complex. The cereblon-binding affinity IC₅₀ of iberdomide is approximately 150 nM. [1]

A panel of multiple myeloma (MM) cell lines (EJM, H929, KMS11, KMS128M, KMS12PE, MM1.S, MM1.R, RPM-8226, U266 cells) showed antiproliferative effects across a range of concentrations when iberdomide (CC-220; 0.01, 0.1, 1, 10 μM; 72-96 hrs) was administered[1].
In all MM cell lines, iberdomide (0.1 μM; 96 hrs) causes apoptosis[1].
On H929 cells, imiberdomide (0.1 μM; 24, 48, and 72 hours) causes time-dependent increases in the G0/G1 and sub-G1 cell cycle fractions[1].
In the KMS12BM line, iberdomide causes rapid Aiolos depletion[1].
In two of the Pomalidomide-resistant (PR) lines with cereblon mutations (EJM/PR and H929/PR), imiberdomide (0.1 μM) exhibits some anti-proliferative activity in addition to decreased levels of cereblon protein[1].
Both parental MM1.S cells and MM1.S/PR cells are equally susceptible to PBMC-mediated killing when exposed to iberdomide (0.1-1000 nM) for 72 hours[1].

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Iberdomide exhibited greater antiproliferative activity than pomalidomide and lenalidomide in a panel of multiple myeloma (MM) cell lines. [1]
In H929 cells (lenalidomide-sensitive) and an acquired lenalidomide-resistant (H929/LR) cell line, the antiproliferative activity order was iberdomide > pomalidomide > lenalidomide. [1]
Treatment with iberdomide induced time-dependent increases in G0/G1 and sub-G1 cell cycle fractions in H929 cells. [1]
Iberdomide induced greater apoptosis than pomalidomide in all tested MM cell lines at a tenfold lower concentration. [1]
Treatment with 0.1 µM iberdomide led to a faster decrease in the protein levels of Ikaros, Aiolos, and c-Myc/IRF4 compared to treatment with 1 µM pomalidomide. [1]
In combination with bortezomib, iberdomide showed synergistic antiproliferative effects in MM1.S cells. [1]
The combination of iberdomide and bortezomib increased the apoptotic fraction to 95% compared to 87% with pomalidomide/bortezomib in MM1.S cells. [1]
Iberdomide combined with daratumumab exhibited greater inhibitory effects on H929 cells than either drug alone in the presence of human-derived complement. [1]
In an ADCC assay, iberdomide enhanced daratumumab-mediated antibody-dependent cellular cytotoxicity, presumably by stimulating NK cells. [1]
Iberdomide induced PBMC-mediated killing of both parental MM1.5 cells and pomalidomide-resistant MM1.5/PR cells in co-culture experiments. [1]
In pomalidomide-resistant (PR) cell lines with reduced but detectable cereblon levels, iberdomide showed modest antiproliferative activity. However, little to no activity was observed in PR lines with very low cereblon (MM1.R/PR, MM1.5/PR, DF15/PR). [1]
In the KMS12BM/PR cell line, only iberdomide (not pomalidomide) was effective at inducing rapid depletion of Aiolos. [1]
The combination of iberdomide and daratumumab showed a more pronounced dose-dependent inhibitory effect on H929/PR cells than either drug alone in complement-dependent cytotoxicity assays. [1]
In KMS12PE/PR cells, the combination of iberdomide and a low concentration of bortezomib (0.25 nM) demonstrated an enhanced antiproliferative effect. [1]

Higher hCRBN expression in hC343 splenocytes following 6 or 24 hours of iberdomide (CC-220; 10 mg/kg; oral gavage) is correlated with deeper IKZF1/3 downregulation in WT (C57BL/6), hC123 or-343 (representing two distinct transgenic founder lines expressing hCRBN), and mCrbn-/- mice[2].

DMSO is used to dissolve iberdomide. The assay uses 20 mM HEPES pH 7, 150 mM NaCl, 0.005% Tween-20 assay buffer, 60 nM 6Xhis-tagged CRBN-DDB1, 30 nM cy5-conjugated cereblon modulator, and 3 nM LanthaScreen Eu-anti-His Tag antibody. The ratio of FRET to non-FRET emission is used to calculate FRET efficiency. FRET is observed by exciting at 340 nm and monitoring emission at 615 nm and 665 nm. Prior to scanning, the DMSO carrier or the competing cereblon modulating compound (iberdomide) is titrated and incubated for ten minutes[1].

For antiproliferative assays, MM cell lines were treated with iberdomide across a range of concentrations, and proliferation was measured using 3H-thymidine incorporation. [1]
Apoptosis was assessed by flow cytometry using Annexin-V and To-Pro-3 staining. Cells were treated with iberdomide, stained, and analyzed for apoptotic fractions. [1]
Western blot analysis was performed to evaluate protein degradation. Cells were treated with iberdomide, lysed, and proteins were separated by SDS-PAGE, transferred to membranes, and probed with antibodies against targets such as Ikaros, Aiolos, ZFP91, c-Myc, and IRF4. Actin was used as a loading control. [1]
For PBMC co-culture killing assays, isolated and CD3-stimulated PBMCs were incubated with iberdomide for 72 hours. These PBMCs were then co-cultured with CFSE-stained MM target cells (parental or resistant) for 4 hours. Target cell apoptosis was evaluated by flow cytometry using Annexin-V and To-Pro-3 staining. [1]
Complement-dependent cytotoxicity (CDC) assays were performed by incubating target cells with iberdomide and daratumumab in the presence of human-derived complement, followed by measurement of cell viability. [1]
Antibody-dependent cellular cytotoxicity (ADCC) assays were conducted. Effector PBMCs were pre-treated with iberdomide and/or daratumumab, then co-cultured with target MM cells. Target cell killing was measured. [1]
Immunohistochemistry (IHC) was used on bone marrow aspirate clots from RRMM patients. Samples were stained for CD138 and cereblon, or for substrates like Ikaros, Aiolos, and ZFP91. H-scores were calculated to quantify protein expression levels. [1]

Pomalidomide (Pom) and iberdomide (CC-220), both with purity greater than 98%, were prepared for use as follows: for in vitro studies, the compounds were dissolved in DMSO; for in vivo oral administration, they were formulated in a vehicle consisting of 0.5% carboxymethylcellulose and 0.25% Tween‑80 in water. Pomalidomide was administered orally at a dose of 50 mg/kg twice daily on days 1–5 and days 8–12, while iberdomide was administered orally at a dose of 10 mg/kg following the same dosing schedule. [2]

Iberdomide (CC-220) is an oral cereblon E3 ligase modulator with favorable pharmacokinetic properties. Following oral administration, exposure increases in a dose‑proportional manner. In healthy subjects, the terminal elimination half‑life is approximately 9 to 13 hours after a single dose. In vitro studies show it has a molecular weight of 449 g/mol, cLogP of 1.1, and Caco‑2 permeability of 5.6 ± 2.5 × 10⁻⁶ cm/s with an efflux ratio of 5.1. Kinetic solubility is 380 ± 28 μM, and it demonstrates good metabolic stability in human liver microsomes (half‑life of 115 minutes) and plasma (half‑life >746 minutes). In MOLT4 cells, iberdomide exhibits an intracellular unbound fraction of 0.06, an intracellular accumulation factor of 9.3, and an intracellular bioavailability of 0.56.

In first‑in‑human studies, iberdomide was tolerated as a single dose up to 6 mg and at 0.3 mg once daily for 4 weeks, with grade 3 asymptomatic neutropenia observed at 1 mg once daily. In a Phase 1/2 trial in heavily pretreated relapsed/refractory multiple myeloma patients (CC‑220‑MM‑001), the recommended Phase 2 dose was established as 1.6 mg. The most common grade ≥3 adverse events in the dose‑expansion cohort (n=107) were neutropenia (45%), anemia (28%), infection (27%), and thrombocytopenia (22%). Venous thromboembolism occurred in approximately 4‑5% of patients. Dose interruptions and reductions were required in about 52% and 19‑24% of patients, respectively, while discontinuation due to adverse events occurred in 5‑7% of patients. One treatment‑related death (sepsis) was reported. Higher iberdomide exposure was associated with a higher probability and earlier occurrence of grade ≥3 neutropenia and thrombocytopenia (p < 0.05).

[1]. Leukemia. 2020 Apr;34(4):1197-1201.

[2]. Blood Cancer Discov. 2021 Jul;2(4):354-369.

[3]. J Med Chem. 2018 Jan 25;61(2):535-542.

Ibelidomide (CC-220) has been used in clinical trials for the treatment of systemic lupus erythematosus. Ibelidomide is a modulator of the E3 ubiquitin ligase complex (containing cereblon (CRL4-CRBN E3 ubiquitin ligase)) and possesses immunomodulatory and pro-apoptotic activities. Upon administration, ibelidomide specifically binds to the cereblon (CRBN) moiety in the ligase complex, thereby affecting the activity of the ubiquitin E3 ligase and targeting certain substrate proteins for ubiquitination modification. This induces the proteasome-mediated degradation of certain transcription factors, including the transcriptional repressors Ikaros (IKZF1) and Aiolos (IKZF3) in T cells. This leads to decreased protein levels of these transcription factors and modulates the immune system, including the activation of T lymphocytes. Furthermore, this also leads to the downregulation of other proteins, including interferon regulatory factor 4 (IRF4), which plays a crucial role in the proliferation of certain cancer cell types. CRBN is a substrate recognition component of the E3 ubiquitin ligase complex and plays a key role in the ubiquitination of certain proteins.

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Drug indications
Therapeutic use of mature B-cell tumors
Iberdomide is described as a new generation cereblon E3 ligase modulator (CELMoD). [1]
It exerts its anti-myeloma activity through cereblon, leading to targeted degradation of substrates such as Ikaros and Aiolos, and downregulation of c-Myc and IRF4. [1]
Compared to pomalidomide, iberdomide exhibits faster substrate degradation, which may be due to its higher binding affinity for cereblon and/or stronger processing capability of the E3 ligase complex. [1]
An ongoing phase 1b/2a clinical trial (NCT02773030) aims to determine the maximum tolerated dose of iberdomide monotherapy or in combination with dexamethasone for patients with relapsed/refractory multiple myeloma (RRMM). [1]
Pharmacodynamic analysis of bone marrow samples from patients showed that iberdomide treatment significantly reduced protein levels of Ikaros, Aiolos, and ZFP91. [1]
In bone marrow samples from RRMM patients who had previously received IMiDs, the expression levels of cereblon protein varied considerably. [1]

C25H27N3O5

449.4990

449.195

449.500

1323403-33-3

1560678-63-8 (HCl);1323403-33-3;

67335295

White to off-white solid powder

1.3±0.1 g/cm3

717.8±60.0 °C at 760 mmHg

387.9±32.9 °C

0.0±2.3 mmHg at 25°C

1.629

1.07

1

6

6

33

732

1

O(C([H])([H])C1C([H])=C([H])C(=C([H])C=1[H])C([H])([H])N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H])C1=C([H])C([H])=C([H])C2C(N(C([H])([H])C=21)[C@]1([H])C(N([H])C(C([H])([H])C1([H])[H])=O)=O)=O

IXZOHGPZAQLIBH-NRFANRHFSA-N

InChI=1S/C25H27N3O5/c29-23-9-8-21(24(30)26-23)28-15-20-19(25(28)31)2-1-3-22(20)33-16-18-6-4-17(5-7-18)14-27-10-12-32-13-11-27/h1-7,21H,8-16H2,(H,26,29,30)/t21-/m0/s1

(S)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

CC-220; CC220; Iberdomide; 1323403-33-3; (S)-3-(4-((4-(Morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; Iberdomida; CC 220.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : 90~125 mg/mL ( 200.22~278.09 mM )
Ethanol : ~5 mg/mL

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.63 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 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 20.8 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.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (4.63 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (4.63 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)