Corubrutinib
Based on 1 Customer Validation
Corubrutinib (BIIB091) is an orally active BTK inhibitor with an IC50 of <0.5 nM, Kd of 0.07 nM, and >500-fold kinome selectivity. Corubrutinib suppresses B cell activation, proliferation, differentiation, antibody production, antigen presentation, cytokine secretion, and myeloid cell effector functions. Corubrutinib exhibits favorable pharmacokinetic and preclinical safety profiles, including low genotoxic potential, minimal hepatotoxicity, and no major transporter or CYP inhibition. Corubrutinib can be used for the research of multiple sclerosis.
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- Pureté : 99.85%
- CAS No.: 2247614-80-6
- Formule: C28H34N10O2
- Masse moléculaire:542.64
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Stockage:Powder -20°C, 3 years , 4°C, 2 years ; In solvent -80°C, 6 months , -20°C, 1 month
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Activité biologique
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Chemical Information
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Solvant et solubilité
- Protocole
- Pureté et documentation
- Références
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Help & FAQs
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Activité biologique
Description
Cellular Effect
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Cell Line
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Type | Value | Description | References |
|---|---|---|---|---|
| Ramos | IC50 |
6.9 nM
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Inhibition of BCR-mediated PLCγ2 phosphorylation (Y1217) in Ramos B cells, pre-incubated for 30 min with titrating concentrations of Corubrutinib then stimulated for 5 min with anti-human IgM.
Inhibition of BCR-mediated PLCγ2 phosphorylation (Y1217) in Ramos B cells, pre-incubated for 30 min with titrating concentrations of Corubrutinib then stimulated for 5 min with anti-human IgM.
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34141433 |
| B cell | IC50 |
5.4 nM
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Inhibition of BCR-mediated CD69 upregulation in human PBMC B cells from healthy donors, pre-incubated for 30 min with titrating concentrations of Corubrutinib then stimulated overnight with polyclonal rabbit F(ab')2 anti-human IgD.
Inhibition of BCR-mediated CD69 upregulation in human PBMC B cells from healthy donors, pre-incubated for 30 min with titrating concentrations of Corubrutinib then stimulated overnight with polyclonal rabbit F(ab')2 anti-human IgD.
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34141433 |
| B cell | IC50 |
87 nM
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Inhibition of BCR-mediated CD69 upregulation in human whole blood B cells from healthy donors, pre-incubated for 30 min with titrating concentrations of Corubrutinib then stimulated overnight with anti-human IgD-dextran or F(ab')2 anti-human IgD.
Inhibition of BCR-mediated CD69 upregulation in human whole blood B cells from healthy donors, pre-incubated for 30 min with titrating concentrations of Corubrutinib then stimulated overnight with anti-human IgD-dextran or F(ab')2 anti-human IgD.
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34141433 |
| Neutrophil | IC50 |
4.5 nM
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Inhibition of FcγR-mediated reactive oxygen species (ROS) generation in purified human neutrophils from healthy donors, pre-incubated for 30 min with titrating concentrations of Corubrutinib then stimulated for 1-2 h with immune complexes (anti-RNP antibodies complexed with RNP antigen).
Inhibition of FcγR-mediated reactive oxygen species (ROS) generation in purified human neutrophils from healthy donors, pre-incubated for 30 min with titrating concentrations of Corubrutinib then stimulated for 1-2 h with immune complexes (anti-RNP antibodies complexed with RNP antigen).
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34141433 |
| Monocyte | IC50 |
5.6 nM
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Inhibition of FcγR-mediated TNFα production in purified human monocytes from healthy donors stimulated overnight with plate-bound human IgG, in the presence of titrating concentrations of Corubrutinib.
Inhibition of FcγR-mediated TNFα production in purified human monocytes from healthy donors stimulated overnight with plate-bound human IgG, in the presence of titrating concentrations of Corubrutinib.
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34141433 |
| Monocyte | IC50 |
8.0 nM
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Inhibition of FcγR-mediated TNFα production in purified human monocytes from healthy donors stimulated overnight with plate-bound anti-human CD16 antibody, in the presence of titrating concentrations of Corubrutinib.
Inhibition of FcγR-mediated TNFα production in purified human monocytes from healthy donors stimulated overnight with plate-bound anti-human CD16 antibody, in the presence of titrating concentrations of Corubrutinib.
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34141433 |
| Monocyte | IC50 |
3.1 nM
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Inhibition of FcγR-mediated TNFα production in purified human monocytes from healthy donors stimulated overnight with plate-bound anti-human CD64 antibody, in the presence of titrating concentrations of Corubrutinib.
Inhibition of FcγR-mediated TNFα production in purified human monocytes from healthy donors stimulated overnight with plate-bound anti-human CD64 antibody, in the presence of titrating concentrations of Corubrutinib.
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34141433 |
| B cell | IC50 |
3 nM
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Inhibition of BTK-dependent early signaling events and downstream cellular effector functions (activation, proliferation, differentiation, and BCR-mediated antigen presentation to T cells) in B cells.
Inhibition of BTK-dependent early signaling events and downstream cellular effector functions (activation, proliferation, differentiation, and BCR-mediated antigen presentation to T cells) in B cells.
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42016388 |
| B cell | IC50 |
106 nM
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Inhibition of BTK-dependent early signaling events and downstream cellular effector functions (activation, proliferation, differentiation, and BCR-mediated antigen presentation to T cells) in B cells.
Inhibition of BTK-dependent early signaling events and downstream cellular effector functions (activation, proliferation, differentiation, and BCR-mediated antigen presentation to T cells) in B cells.
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42016388 |
| B cell | IC50 |
22 nM
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Reduction of proliferation of OVA32-339-specific T cells in response to OVA-targeted B cells.
Reduction of proliferation of OVA32-339-specific T cells in response to OVA-targeted B cells.
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34734694 |
In Vitro
Corubrutinib (BIIB091) potently and selectively inhibits purified human BTK kinase activity with an IC50 of 450 pM and >500-fold selectivity over other kinases[1].
Corubrutinib demonstrates high kinome selectivity, with >500-fold preference for BTK over other kinases, and no off-target activity against a panel of 68 physiologically relevant targets[2].
Corubrutinib (30 min) potently inhibits purified human BTK enzyme activity with an IC50 < 0.5 nM in a biochemical activity assay[3].
Corubrutinib (30 min) inhibits phosphorylated BTK in human whole blood with an IC50 of 24 nM[3].
Corubrutinib (1 μM) binds human BTK with a Kd of 0.07 nM and exhibits >500-fold selectivity for BTK over all tested off-target kinases in a KINOMEscan binding assay[3].
Corubrutinib inhibits PLCγ2 phosphorylation in the Ramos human B-cell line with an IC50 of 6.9 nM[3].
Corubrutinib (titrating concentrations; 30 min pre-incubation, 5 min stimulation) inhibits BCR-mediated PLCγ2 phosphorylation (Y1217) in Ramos B cells with an IC50 of 6.9 nM[1].
Corubrutinib (100 nM; 3-5 days) potently blocks human primary B-cell proliferation induced by multiple BTK-dependent stimuli, with maximal effect when present at the time of stimulation[1].
Corubrutinib potently inhibits BTK-dependent signaling and cellular functions in B cells and myeloid cells with IC50s of 3 to 106 nM, and blocks BCR-mediated antigen presentation to T cells[2].
Corubrutinib potently inhibits signaling downstream of both B cell receptors and Fc receptors in vitro[2].
Corubrutinib (30 min pre-incubation; 18-22 h stimulation incubation) inhibits BCR-mediated CD69 expression on human CD19+ B cells in whole blood with an IC50 of 71 nM[3].
Corubrutinib inhibits anti-IgM-stimulated CD69 activation in human PBMCs with an IC50 of 5.4 nM[3].
Corubrutinib inhibits BCR-mediated antigen presentation to OVA32-339-specific T cells with an IC50 of 22 nM[3].
Corubrutinib (titrating concentrations; 30 min pre-incubation, 1-2 h stimulation) inhibits FcγR-mediated ROS generation in purified human neutrophils from healthy donors with an average IC50 of 4.5 nM[1].
Corubrutinib inhibits FcγR-induced ROS production in purified human primary neutrophils with an IC50 of 4.5 nM[3].
Corubrutinib (titrating concentrations; 30 min pre-incubation, 10 min IL-3 stimulation, 20 min anti-IgE stimulation) inhibits FcεRI-mediated basophil degranulation in human whole blood from healthy donors with an average IC50 of 106 nM[1].
Corubrutinib inhibits FcεR-induced CD63 expression on human basophils in whole blood with an IC50 of 82 nM[3].
Corubrutinib (titrating concentrations; overnight) inhibits FcγR-mediated TNFα production in purified human monocytes from healthy donors, with average IC50 values ranging from 3.1 nM to 8.0 nM depending on the FcγR agonist[1].
Corubrutinib inhibits FcγR-mediated TNFα secretion in human monocytes, with IC50 values ranging from 1.3 nM to 8.0 nM depending on the FcγR agonist used[3].
Corubrutinib (0.37-10 μM) selectively inhibits BTK-dependent B cell functions in human primary cell culture systems, with minimal off-target effects at concentrations up to 10 μM[3].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only. Further protocols information, click here.
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Cell Line:Human B cells (isolated from PBMCs)
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Concentration:100 nM
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Incubation Time:3-5 days
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Result:Blocked B-cell proliferative responses induced by all stimuli.
Parmacokinetics
| Species | Dose | Route | T1/2 | AUCinf | CL | Tmax | Cmax | Bioavailability | Vdss |
|---|---|---|---|---|---|---|---|---|---|
| Rat[3] | 1 mg/kg | i.v. | 2.1 h | 748 | 10 mL/min/kg | / | / | / | / |
| Rat[3] | 5 mg/kg | p.o. | / | 1522 ng/mL·h | / | 0.9 h | 693 ng/mL | 42 % | 0.4 L/kg |
| Cynomolgus Monkey[3] | 1 mg/kg | i.v. | 1.1 h | 943 | 18 mL/min/kg | / | / | / | / |
| Cynomolgus Monkey[3] | 5 mg/kg | p.o. | / | 1446 ng/mL·h | / | 0.33 h | 1104 ng/mL | 31 % | 0.7 L/kg |
| Dog[3] | 1 mg/kg | i.v. | 6.0 h | 1675 ng/mL·h | 12 mL/min/kg | / | / | / | / |
| Dog[3] | 5 mg/kg | p.o. | / | 6075 ng/mL·h | / | 1.6 h | 1440 ng/mL | 89 % | 1.7 L/kg |
In Vivo
Corubrutinib (0.03-30 mg/kg; p.o.; b.i.d; 10 days) potently inhibits thymus-independent antibody responses in C57BL/6 mice, with an ED50 of 1.95 mg/kg for reduction of NP-specific IgM titres[1].
Corubrutinib (1-60 mg/kg; p.o.; b.i.d; 8 days) dose-dependently inhibits germinal center B-cell formation in C57BL/6 mice immunised with sheep red blood cells, with maximal inhibition of 49-64% at doses of 10 mg/kg and above, without affecting total B-cell survival[1].
Corubrutinib (0.03-30 mg/kg; p.o.; twice daily; 10 days) dose-dependently inhibits BTK-dependent B-cell activation in the TI-2 mouse model, with an ED50 of 1.95 mg/kg/daily for reducing NP-specific IgM antibody titers, and achieves 90% efficacy when maintaining > 85% pBTK inhibition and > 60% CD69 inhibition[3].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:C57BL/6 mice[1]
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Dosage:3, 30 mg/kg
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Administration:p.o.; single dose
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Result:Inhibited 499 out of 746 differentially expressed genes (DEGs) comprising the IgD-induced B-cell activation signature at 3 mg/kg.
Inhibited 686 out of 746 DEGs comprising the IgD-induced B-cell activation signature at 30 mg/kg.
Reduced CD69 protein levels on B cells.
Inhibited key pathways including BCR signaling, NFAT signaling, and cell cycle regulation at 30 mg/kg.
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Animal Model:C57BL/6 mice[1]
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Dosage:0.03, 0.1, 0.3, 1.0, 3.0, 10.0, 30.0 mg/kg
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Administration:p.o.; b.i.d; 10 days
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Result:Inhibited serum NP-specific IgM antibody titres dose-dependently, with a calculated ED50 of 1.95 mg/kg.
Achieved maximal inhibition of antibody titres at doses of 10 mg/kg and above.
Inhibited basal BTK autophosphorylation in whole blood dose-dependently, with an in vivo IC50 of 3.1 nM.
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Animal Model:C57BL/6 mice[1]
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Dosage:1.0, 3.0, 10.0, 30.0, 60.0 mg/kg
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Administration:p.o.; b.i.d; 8 days
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Result:Inhibited the frequency of splenic germinal center B cells dose-dependently, with maximal inhibition levels of 49% to 64% observed at doses of 10 mg/kg and above.
Left the frequency of total splenic B cells unchanged across all doses tested.
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Animal Model:C57BL/6[3]
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Dosage:0.03, 0.1, 0.3, 1.0, 10, 30 mg/kg
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Administration:p.o.; twice daily; 10 days
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Result:Reduced NP-specific IgM antibody titers by 34% at 0.03 mg/kg, 44% at 0.1 mg/kg, 59% at 0.3 mg/kg, 59% at 1 mg/kg, 77% at 10 mg/kg, and 88% at 30 mg/kg.
Achieved an ED50 of 1.95 mg/kg/daily for reduction of anti-NP IgM antibody titers.
Inhibited phosphorylated BTK (pBTK) in whole blood with an in vivo IC50 of 3 nM.
Correlated 90% inhibition of NP-specific IgM titers with > 85% pBTK inhibition and > 60% CD69 inhibition over the dosing interval.
Essai clinique
| NCT Number | Sponsor | Condition | Start Date |
Phase
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|---|---|---|---|---|
| NCT01329991 | Plexxikon| | 2011-05 | PHASE1 |
Chemical Information
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CAS No. 2247614-80-6
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Appearance Solid
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Masse moléculaire 542.64
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Formule C28H34N10O2
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Color Light yellow to yellow
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SMILES
O=C(C1=CN(C(C)(C)C)N=N1)N[C@H]2C3=CC=C(C4=CC=NC(NC5=CN(C)N=C5)=N4)C=C3CN(C6COC6)CC2
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Synonyms
BIIB091
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Livraison
Room temperature in continental US; may vary elsewhere.
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Stockage
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Solvant et solubilité
In Vitro:
DMSO : 125 mg/mL (230.36 mM; Need ultrasonic; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
In Vivo:
Select the appropriate dissolution method based on your experimental animal and administration route.
- For the following dissolution methods, please ensure to first prepare a clear stock solution using an In Vitro approach and then sequentially add co-solvents:
- To ensure reliable experimental results, the clarified stock solution can be appropriately stored based on storage conditions. As for the working solution for In Vivo experiments, it is recommended to prepare freshly and use it on the same day.
- The percentages shown for the solvents indicate their volumetric ratio in the final prepared solution. If precipitation or phase separation occurs during preparation, heat and/or sonication can be used to aid dissolution.
Add each solvent one by one: 10% DMSO 40% PEG300 5% Tween-80 45% Saline
Solubility: ≥ 2.08 mg/mL (3.83 mM); Clear solution
This protocol yields a clear solution of ≥ 2.08 mg/mL (saturation unknown).
Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (20.8 mg/mL) to 400 μL PEG300, and mix evenly; then add 50 μL Tween-80 and mix evenly; then add 450 μL Saline to adjust the volume to 1 mL.
Preparation of Saline: Dissolve 0.9 g sodium chloride in ddH₂O and dilute to 100 mL to obtain a clear Saline solution.
Add each solvent one by one: 10% DMSO 90% (20% SBE-β-CD in Saline)
Solubility: ≥ 2.08 mg/mL (3.83 mM); Clear solution
This protocol yields a clear solution of ≥ 2.08 mg/mL (saturation unknown).
Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (20.8 mg/mL) to 900 μL 20% SBE-β-CD in Saline, and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C, storage for one week): 2 g SBE-β-CD powder is dissolved in 10 mL Saline, completely dissolve until clear.
In Vivo Dissolution Calculator
Please enter the basic information of animal experiments:
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Recommended: Prepare an additional quantity of animals to account for potential losses during experiments.
Please enter your animal formula composition:
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%DMSO +
Recommended: Keep the proportion of DMSO in working solution below 2% if your animal is weak.
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%+
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+%Tween-80 + +
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%Saline +
The co-solvents required include: DMSO, . All of co-solvents are available by MedChemExpress (MCE). , Tween 80. All of co-solvents are available by MedChemExpress (MCE).
Working solution concentration: 0.22 mg/mL
Method for preparing stock solution: mg drug dissolved in μL DMSO. Stock solution concentration: mg/mL.
1. Take μL DMSO stock solution;
2. Add μL .
μL , mix evenly;
3. Then add μL Tween 80, mix evenly;
4. Then add μL
Please ensure that the stock solution in the first step is dissolved to a clear state, and add co-solvents in sequence. You can use ultrasonic heating (ultrasonic cleaner, recommended frequency 20-40 kHz), vortexing, etc. to assist dissolution.
Protocole
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Research Protocol for Inflammation-related Diseases
The NLRP3 inflammasome is a cytosolic innate immune signaling platform that integrates priming signals and danger-signal activation to promote caspase-1 activation, maturation of IL-1β and IL-18, and gasdermin D-mediated pyroptotic cell death. The core experimental logic is to determine whether inflammatory disease phenotypes are driven by increased NLRP3 expression, ASC-containing inflammasome assembly, caspase-1 cleavage, GSDMD cleavage, and extracellular release of IL-1β/IL-18 rather than by nonspecific cell injury alone. The pathway is strongly linked to inflammation-related disease phenotypes because monosodium urate crystals activate NALP3/NLRP3 inflammasome signaling in gout-like crystal inflammation, cholesterol crystals activate NLRP3 inflammasomes in atherogenesis models, and DSS-induced intestinal inflammation has been reported to involve NLRP3 inflammasome activity. However, experimental colitis studies also show context-dependent protective effects of NLRP3 inflammasome co
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Hepatotoxicity Study
This protocol evaluates hepatotoxicity using complementary in vivo mouse APAP acute liver injury and in vitro hepatocyte-based cytotoxicity readouts. In vivo APAP injury is assessed by serum ALT/AST, liver histology, hepatic glutathione, protein adducts, necrosis, inflammation, and regeneration-related endpoints. In vitro hepatotoxicity is assessed by loss of viability, leakage of ALT/AST/LDH, oxidative-stress markers, mitochondrial function, nuclear morphology, intracellular calcium, and high-content imaging endpoints.
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Genotoxicity/Mutagenicity Study
The bacterial reverse mutation assay detects point mutations that restore amino-acid prototrophy in auxotrophic Salmonella typhimurium or Escherichia coli tester strains; after exposure to a test article, mutagenic activity is read out as an increased number of revertant colonies on minimal agar compared with the vehicle control. The assay uses tester strains with different mutation targets so that base-substitution and frameshift mutagens can be detected, and testing is performed with and without exogenous mammalian metabolic activation because some chemicals require biotransformation to become mutagenic.
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Cell Viability Determination by MTT Colorimetric Assay
The following protocol uses the MTT colorimetric assay as a classic literature-established method for assessing cell viability/metabolic activity in cultured mammalian cells. MTT[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] is reduced by metabolically active cells to a colored formazan product; the amount of formazan is quantified spectrophotometrically and provides an indirect measure of metabolically active viable cells. Importantly, MTT reduction reflects cellular oxidoreductase/metabolic activity rather than an absolute direct count of living cells, so changes in cellular metabolism can alter the signal independently of cell number.
Pureté et documentation
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Fiche technique (301 KB)
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SDS (251 KB)
- English - EN (251 KB)
- Français - FR (251 KB)
- Deutsch - DE (251 KB)
- Norwegian - NO (251 KB)
- Español - ES (251 KB)
- Swedish - SV (251 KB)
- Italian - IT (251 KB)
- Korean - KR (251 KB)
- Portuguese - PT (251 KB)
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Instruction de manipulation (2659 KB)
Références
[1]. Bame E, et al. Next-generation Bruton's tyrosine kinase inhibitor BIIB091 selectively and potently inhibits B cell and Fc receptor signaling and downstream functions in B cells and myeloid cells. Clinical & translational immunology. 2021;10(6):e1295. [Content Brief]
[3]. Hopkins BT, et al. Discovery and Preclinical Characterization of BIIB091, a Reversible, Selective BTK Inhibitor for the Treatment of Multiple Sclerosis. Journal of medicinal chemistry. 2022 Jan 27;65(2):1206-1224. [Content Brief]
Complete Stock Solution Preparation Table
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
| Optional Solvent | Concentration Solvent Mass | 1 mg | 5 mg | 10 mg | 25 mg |
|---|---|---|---|---|---|
| DMSO | 1 mM | 1.8428 mL | 9.2142 mL | 18.4284 mL | 46.0711 mL |
| 5 mM | 0.3686 mL | 1.8428 mL | 3.6857 mL | 9.2142 mL | |
| 10 mM | 0.1843 mL | 0.9214 mL | 1.8428 mL | 4.6071 mL | |
| 15 mM | 0.1229 mL | 0.6143 mL | 1.2286 mL | 3.0714 mL | |
| 20 mM | 0.0921 mL | 0.4607 mL | 0.9214 mL | 2.3036 mL | |
| 25 mM | 0.0737 mL | 0.3686 mL | 0.7371 mL | 1.8428 mL | |
| 30 mM | 0.0614 mL | 0.3071 mL | 0.6143 mL | 1.5357 mL | |
| 40 mM | 0.0461 mL | 0.2304 mL | 0.4607 mL | 1.1518 mL | |
| 50 mM | 0.0369 mL | 0.1843 mL | 0.3686 mL | 0.9214 mL | |
| 60 mM | 0.0307 mL | 0.1536 mL | 0.3071 mL | 0.7679 mL | |
| 80 mM | 0.0230 mL | 0.1152 mL | 0.2304 mL | 0.5759 mL | |
| 100 mM | 0.0184 mL | 0.0921 mL | 0.1843 mL | 0.4607 mL |
Corubrutinib Related Classifications
HY-139984 Related Classifications
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