| Size | Price | Stock | Qty |
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| Targets |
CRBN/cereblon
Mezigdomide is a cereblon E3 ubiquitin ligase modulator (CELMoD) that binds to cereblon (CRBN), the substrate receptor of the CRL4CRBN E3 ubiquitin ligase complex. The compound functions as a molecular glue, recruiting the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) to the CRL4CRBN E3 ubiquitin ligase, leading to their ubiquitination and subsequent degradation by the proteasome. Mezigdomide binds to cereblon with high affinity (IC50 = 0.03 μM in a FRET assay). By degrading IKZF1 and IKZF3, mezigdomide disrupts multiple myeloma cell survival and proliferation pathways. The compound also recruits ZFP91 targets to the CRL4CRBN E3 ubiquitin ligase. |
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| ln Vitro |
Mezigdomide is a novel cereblon E3 ligase modulator (CELMoD) with enhanced autonomous cell-killing activity in multiple myeloma cells . It exhibits a unique and rapid degradation profile by driving the formation of the protein-protein interaction between Aiolos (IKZF3) and cereblon, inducing targeted docking to the CRL4-CRBN E3 ubiquitin ligase complex . The mezigdomide-dependent binding of Aiolos and Ikaros to cereblon leads to polyubiquitination and ultimately proteasome-mediated degradation of these transcription factors . Rapid and extensive loss of Aiolos and Ikaros in sensitive cells, such as multiple myeloma cells, results in apoptosis and subsequent cell death . In cell-based studies using H929 R10-1 cells, mezigdomide was evaluated at concentrations of 1 nM, 10 nM, and 100 nM over 4 and 72 hours .
Another modulator of the brain is mezigdomide. T cell activation and IFN-γ and IL-2 production were elevated in PBMC cultures following mezigdomide-induced deletion of Aiolos and Ikaros. Mezigdomide works well against drug-resistant cell lines such as CC-5013, CC-4047, and CC-220. It exhibits strong synergy with NSC 34521 and induces cell death as a single agent [1]. Mezigdomide is a potent and selective cereblon E3 ubiquitin ligase modulator that induces degradation of IKZF1 and Aiolos in lenalidomide-resistant cells at concentrations of 1, 10, and 100 nM. It binds to cereblon with an IC50 of 0.03 μM in a FRET assay. Mezigdomide works well against drug-resistant cell lines such as CC-5013, CC-4047, and CC-220. The compound induces cell death as a single agent. It has antiproliferative and antitumor activity. |
| ln Vivo |
Mezigdomide was evaluated in efficacy models to assess tumor growth inhibition in tumor-bearing mice . When tumors reached approximately 150 mm³, mice were randomized and treated once daily orally with vehicle control or various doses of mezigdomide . Both the 3 mg/kg and 10 mg/kg doses achieved near-maximal response in this model, while the lowest tested dose (1 mg/kg) showed 75% reduction in tumor volume by the end of the study . In clinical studies, mezigdomide plus dexamethasone demonstrated promising efficacy in heavily pretreated patients with relapsed/refractory multiple myeloma, with an overall response rate of 41% (95% CI, 31-51) and a median duration of response of 7.6 months .
In vivo, mezigdomide demonstrates potent antitumor activity in preclinical models of multiple myeloma, including models resistant to lenalidomide and pomalidomide. As an orally active compound, it can be administered orally for convenient dosing. Mezigdomide induces degradation of IKZF1 and IKZF3 in tumor tissues, leading to growth inhibition and apoptosis. The compound is being developed for the treatment of relapsed/refractory multiple myeloma and has shown promising clinical activity in early-phase trials. |
| Enzyme Assay |
Cereblon binding assays for mezigdomide are performed using FRET (Förster resonance energy transfer) or SPR (surface plasmon resonance) technologies. Recombinant cereblon protein is incubated with varying concentrations of mezigdomide and a fluorescently labeled probe that binds to cereblon. The FRET signal change upon compound binding is measured. IC50 values are calculated from concentration-response curves. Ubiquitination assays measure the ability of mezigdomide to promote IKZF1 or IKZF3 ubiquitination in the presence of E1, E2, and CRL4CRBN E3 ligase complex.
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| Cell Assay |
Cellular assays for mezigdomide typically employ multiple myeloma cell lines, including lenalidomide-sensitive and -resistant lines (e.g., H929 and H929 R10-1 cells). Cells are treated with varying concentrations of mezigdomide for 24-72 hours. IKZF1 and IKZF3 protein levels are assessed by Western blot to confirm degradation. Cell viability is assessed using MTT or CellTiter-Glo assays. Apoptosis is evaluated by Annexin V/PI staining. Cell cycle analysis is performed by propidium iodide staining. The compound's activity against drug-resistant cell lines is compared with lenalidomide and pomalidomide.
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| Animal Protocol |
In vivo efficacy is evaluated in mouse xenograft models of multiple myeloma, including models resistant to lenalidomide. Tumor-bearing mice are treated with mezigdomide orally at various doses. Tumor volumes are measured every 2-3 days. Pharmacodynamic markers such as IKZF1 and IKZF3 protein levels are measured in tumor tissues to confirm target engagement. Body weight and clinical signs are monitored for tolerability. The compound's antitumor activity is compared with standard of care agents.
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| ADME/Pharmacokinetics |
Mezigdomide demonstrates linear pharmacokinetics with a linear dose-exposure relationship in healthy subjects . A two-compartment linear model with first-order absorption and lag time best describes its pharmacokinetic profile . Key population pharmacokinetic parameters are as follows :
Absorption rate constant (kₐ): 1.18 h⁻¹ Lag time: 0.423 h Central volume of distribution (V₁): 440 L Clearance (CL): 35.1 L/h Peripheral volume of distribution (V₂): 243 L Intercompartmental clearance (Q): 36.8 L/h Food Effect: A high-fat meal increases oral bioavailability by approximately 30% . Acid-Reducing Agent Effect: Co-administration with a proton pump inhibitor (PPI) decreases oral bioavailability by approximately 64% . Drug-Drug Interactions: Mezigdomide is a sensitive CYP3A4 substrate . Co-administration with the strong CYP3A4 inhibitor itraconazole increases mezigdomide area under the curve (AUC) 14.1-fold, while the strong CYP3A4 inducer rifampin reduces AUC by 95% . When coadministered with moderate CYP3A4 inhibitors (e.g., fluconazole), mezigdomide clearance is reduced approximately 0.38-fold; with strong CYP3A4 inhibitors (e.g., posaconazole, voriconazole), clearance is reduced 0.15- and 0.11-fold, respectively . Renal Impairment: Mezigdomide is mainly eliminated through hepatic metabolism, with renal elimination playing a smaller role . Mezigdomide exposures in patients with mild or moderate renal impairment are consistent with those in patients with normal renal function, and no dose adjustments are required for patients with mild to moderate renal impairment . Solubility: Mezigdomide is a weak-base compound with pH-dependent solubility. Solubility at pH 1 is 0.133 mg/mL, which decreases approximately 100-fold to 0.001 mg/mL at pH 5 . Mezigdomide is orally active with good bioavailability. It has molecular formula C32H30FN5O4 and molecular weight 567.6 (approximate). The compound is soluble in DMSO (≥40 mg/mL). It should be stored at -20°C for long-term stability. Mezigdomide is a potent cereblon modulator with favorable drug-like properties supporting oral dosing. Pharmacokinetic studies have characterized absorption, distribution, metabolism, and excretion in preclinical species and humans. |
| Toxicity/Toxicokinetics |
In the Phase 1/2 CC-92480-MM-001 trial of mezigdomide plus dexamethasone in relapsed/refractory multiple myeloma (N=101 in the dose-expansion cohort), the most common adverse events were :
Neutropenia: 77% (grade 3: 22%, grade 4: 54%) Infection: 65% (grade 3: 29%, grade 4: 6%) Anemia: 52% (grade 3: 35%, grade 4: 1%) Thrombocytopenia: 43% Febrile neutropenia occurred in 15% of patients (grade 3: 13%, grade 4: 2%) . Most adverse events were reversible . Growth factor support was administered to 3/4 of patients . Dose reductions of mezigdomide due to adverse events occurred in 29% of patients, and treatment discontinuation occurred in 6% . In the dose-expansion cohort, all patients had triple-class-refractory multiple myeloma, 30% had received prior anti-BCMA therapy, and 40% had plasmacytomas . The overall response rate was 41%, with a median progression-free survival of 4.4 months . Among patients with prior anti-BCMA therapy, the overall response rate was 50% . Dose-Limiting Toxicities: The most common dose-limiting toxicities were neutropenia and febrile neutropenia . The recommended Phase 2 dose was established as 1.0 mg once daily on days 1-21 of each 28-day cycle in combination with dexamethasone . Preclinical toxicology studies for mezigdomide are ongoing as part of clinical development. As a cereblon modulator, potential toxicities may include myelosuppression, infections, and gastrointestinal effects, similar to other immunomodulatory drugs. The compound has been evaluated in preclinical models with acceptable tolerability. Standard safety pharmacology, genotoxicity, and repeated-dose toxicity studies are being conducted for regulatory approval. |
| References | |
| Additional Infomation |
Mezigdomide is being investigated in the clinical trial NCT05372354 (a study evaluating the safety, drug concentration, and efficacy of CC-92480 (BMS-986348) in combination with other therapies for patients with relapsed or refractory multiple myeloma). Mezigdomide is a modulator of the E3 ubiquitin ligase complex (containing cereblon, i.e., CRL4-CRBN E3 ubiquitin ligase) and has potential immunomodulatory and antitumor activities. After administration, mezigdomide specifically binds to cereblon (CRBN), thereby affecting the activity of the ubiquitin E3 ligase and targeting certain substrate proteins for ubiquitination. This induces the degradation of certain transcription factors via the proteasome, some of which are transcriptional repressors in T cells. This leads to regulation of the immune system, including T lymphocyte activation and downregulation of the activity of other proteins, some of which play a key role in the proliferation of certain cancer cell types. CRBN is a substrate recognition component of the CRL4-CRBN E3 ubiquitin ligase complex and plays a crucial role in the ubiquitination of certain proteins.
Drug Indications Treatment of mature B-cell tumors Mezigdomide (CC-92480) is a novel, selective, and active cereblon E3 ubiquitin ligase modulator (CELMoD). It is being developed for the treatment of multiple myeloma. Mezigdomide binds to cereblon with high affinity and induces degradation of IKZF1 and IKZF3. The compound works well against drug-resistant cell lines and induces cell death as a single agent. It is a molecular glue that recruits target proteins to the CRL4CRBN E3 ubiquitin ligase. |
| Molecular Formula |
C32H30FN5O4
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|---|---|
| Molecular Weight |
567.6101
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| Exact Mass |
567.228
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| Elemental Analysis |
C, 67.71; H, 5.33; F, 3.35; N, 12.34; O, 11.27
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| CAS # |
2259648-80-9
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| PubChem CID |
137379043
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| Appearance |
White to off-white solid powder
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| LogP |
2.9
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
42
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| Complexity |
1050
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C1CC(=O)NC(=O)[C@H]1N2CC3=C(C2=O)C=CC=C3OCC4=CC=C(C=C4)CN5CCN(CC5)C6=C(C=C(C=C6)C#N)F
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| InChi Key |
YTINZZFBHWSAGL-NDEPHWFRSA-N
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| InChi Code |
InChI=1S/C32H30FN5O4/c33-26-16-23(17-34)8-9-27(26)37-14-12-36(13-15-37)18-21-4-6-22(7-5-21)20-42-29-3-1-2-24-25(29)19-38(32(24)41)28-10-11-30(39)35-31(28)40/h1-9,16,28H,10-15,18-20H2,(H,35,39,40)/t28-/m0/s1
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| Chemical Name |
(S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile
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| Synonyms |
Mezigdomide; CC-92480; Mézigdomide; Mezigdomide; 2259648-80-9; CC-92,480; Mezigdomide [USAN]; LA88IH4O02;CC 92,480; Mezigdomida; CC92480; Mezigdomidum
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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 : ~5 mg/mL (~8.81 mM)
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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 | 1.7618 mL | 8.8089 mL | 17.6177 mL | |
| 5 mM | 0.3524 mL | 1.7618 mL | 3.5235 mL | |
| 10 mM | 0.1762 mL | 0.8809 mL | 1.7618 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.
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