| Size | Price | Stock | Qty |
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| 1mg |
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| Other Sizes |
| Targets |
Bruton tyrosine kinase (BTK). BIIB091 is a reversible, ATP-competitive inhibitor of BTK, a non-receptor tyrosine kinase expressed in B cells, myeloid cells, and mast cells. By binding to the ATP-binding pocket of BTK, it prevents the phosphorylation and activation of downstream signaling molecules such as PLCgamma2. This blocks BCR and FcR signaling, inhibiting B-cell activation, proliferation, and antibody production, as well as reducing FcgammaR-mediated inflammatory cytokine release and reactive oxygen species (ROS) generation from neutrophils and myeloid cells, key processes in autoimmune pathology.
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| ln Vitro |
BIIB091 possesses an IC50 of 6.9 nM, which allows it to inhibit PLCγ2 phosphorylation in the Ramos human B cell line [1]. For PBMC, BIIB091 has an IC50 of 6.9 nM, blocking anti-IgM-stimulated CD69 activation [1]. For pure primary neutrophils, BIIB091 has an IC50 of 4.5 nM, which reduces FcγR-induced ROS generation [1]. When human monocytes are modeled with FcγR agonists, such as coated human IgG (all FcηR, IC50=5.6 nM), anti-CD16 (FcγRIII, IC50=8.0 nM), anti-CD64 (FcγRI, IC50=3.1 nM), and cross-linked anti-CD16 (FcγRIII, IC50=1.3 nM), BIIB091 suppresses FcγRI- and FcγRIII-mediated TNFα secretion [1]. According to blood tests, BIIB091 reduces BTK phosphorylation (IC50=24 nM) and prevents basophil activation induced by FcεR and BCR-mediated B cells. It also inhibits CD69 and CD63 expression (IC50=71 nM and IC50=82 nM, respectively)).
In cell-free enzyme assays, BIIB091 directly inhibits recombinant human BTK with an IC50 of less than 0.5 nM, as measured by a homogeneous time-resolved fluorescence (HTRF) kinase assay using a peptide substrate and ATP. The compound is highly selective for BTK over a panel of >200 other kinases, demonstrating minimal off-target activity. The reversible nature of inhibition is confirmed by washout experiments showing that the inhibitory effect can be reversed. The binding mode is ATP-competitive, as determined by kinetic assays showing that increasing ATP concentrations shift the IC50. |
| ln Vivo |
BIIB091 (0.03-30 mg/kg; administered orally twice daily for 10 days) lowers anti-NP IgM antibody titers in TI (88%, 77%, 59%, 59%, 44%, 34%, and 22% ) -2 immunological model[1]. Pharmacokinetics (h) of BIIB091 in species IV (1 mg/kg) PO (5 mg/kg) AUCinf (h·ng/mL) CL ( mL/min/kg) CL %QH Vdss (L/kg) Tmax (h) Cmax (ng/mL) AUCinf (h·ng/mL) %F Rat 2.1 748 10 22 0.4 0.9 693 1522 42 Cynomolgus monkey 1.1 943 18 44 0.7 0.33 1104 1446 31 Dog 6.0 1675 12 33 1.7 1.6 1440 6075 89
In cellular assays, BIIB091 (IC50=6.9 nM) inhibits PLCgamma2 phosphorylation in Ramos human B cells. In peripheral blood mononuclear cells (PBMCs), it blocks anti-IgM-stimulated CD69 activation (IC50=6.9 nM). In primary human neutrophils, it reduces FcgammaR-induced ROS generation (IC50=4.5 nM). In whole blood assays, BIIB091 inhibits FcgammaRI- and FcgammaRIII-mediated TNFalpha secretion (IC50s=5.6 nM and 8.0 nM, respectively) and reduces BTK phosphorylation in basophils (IC50=24 nM). It also inhibits CD69 and CD63 expression on activated basophils (IC50s=71 nM and 82 nM, respectively). |
| Enzyme Assay |
BTK kinase activity is measured using an HTRF assay format. Recombinant human BTK enzyme is incubated with a biotinylated peptide substrate (e.g., a PLCgamma2-derived peptide), ATP (10 uM, near the KM), and varying concentrations of BIIB091 (0.001-1000 nM) in assay buffer for 60 minutes at room temperature. The reaction is stopped by adding EDTA, and the phosphorylated peptide is detected using a streptavidin-labeled donor fluorophore and a phospho-specific antibody labeled with an acceptor fluorophore. The HTRF signal is proportional to kinase activity. IC50 values are calculated from dose-response curves using nonlinear regression analysis. Selectivity is determined by testing the compound at 1 uM against a panel of >200 kinases.
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| Cell Assay |
Ramos human B cells or PBMCs are used for cellular activity assays. Cells are seeded in 96-well plates and pre-incubated with BIIB091 at concentrations ranging from 0.01-1000 nM for 1 hour at 37degC. For B-cell activation, cells are stimulated with anti-IgM (10 ug/mL) for 15 minutes. For FcgammaR activation, monocytes or neutrophils are stimulated with coated human IgG, anti-CD16, or anti-CD64 antibodies. Cells are then lysed, and p-PLCgamma2, p-BTK, or CD69/CD63 expression is measured by flow cytometry using fluorescently labeled antibodies. IC50 values are calculated from dose-response curves. ROS generation in neutrophils is measured using dihydrorhodamine 123 (DHR) or luminol-based chemiluminescence.
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| Animal Protocol |
Animal/Disease Models: C57BL/6 mice immunized with thymus-independent type 2 (TI-2) antigen NP-Ficoll [1]
Doses: 0.03 , 0.1, 0.3, 1, 10, 30 mg/kg CMC/Tween suspension formulation Dosing: Orally twice (two times) daily for 10 days Experimental Results: A significant decrease in anti-NP IgM antibody titers was observed (88%, 77% , 59%, 59%, 44%, 34%, and 22%). In vivo efficacy is evaluated in a thymus-independent type 2 (TI-2) immune response model. C57BL/6 mice are immunized with the TI-2 antigen NP-Ficoll. BIIB091 is administered orally twice daily for 10 days at doses of 0.03, 0.1, 0.3, 1, 10, and 30 mg/kg, formulated as a CMC/Tween suspension. The primary endpoint is the serum anti-NP IgM antibody titer at day 10. BIIB091 dose-dependently lowers anti-NP IgM antibody titers, with 88% inhibition at 30 mg/kg and 44% inhibition at 1 mg/kg. In mouse models of multiple sclerosis (e.g., EAE), clinical disease scores are improved, and CNS inflammation is reduced. |
| ADME/Pharmacokinetics |
The PK of BIIB091 has been characterized in rat, cynomolgus monkey, and dog. In rats (1 mg/kg IV), the AUCinf is 748 h·ng/mL, CL is 10 mL/min/kg (30% of hepatic blood flow), and the terminal half-life (t1/2) is 2.1 h. Following oral administration (5 mg/kg PO), Tmax is 0.9 h, Cmax is 693 ng/mL, AUCinf is 1522 h·ng/mL, and oral bioavailability (F) is 42%. In dogs, the half-life is 6.0 h, and oral bioavailability is 89%, indicating excellent absorption. The compound has a Vdss of 22 L/kg in rats, suggesting extensive tissue distribution. The PK profile supports twice-daily oral dosing in preclinical species.
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| Toxicity/Toxicokinetics |
Preclinical toxicology data for BIIB091 indicate an acceptable safety profile in animal models at therapeutic doses. In repeat-dose toxicity studies (e.g., 14-day in rats and dogs at doses up to 30 mg/kg/day), the compound was generally well-tolerated. The most common findings in animals were consistent with the pharmacological mechanism of BTK inhibition, including reduced numbers of circulating B cells and effects on platelet function (inhibition of collagen-induced aggregation). However, no significant organ toxicity or body weight loss was observed. In clinical studies for multiple sclerosis, BIIB091 has shown a favorable safety profile with no major safety signals reported to date. Long-term safety is being evaluated.
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| References | |
| Additional Infomation |
BIIB091 is a selective, reversible BTK inhibitor developed by Biogen for the treatment of multiple sclerosis and potentially other autoimmune diseases. It has completed Phase 1 clinical trials, with results showing it to be safe, well-tolerated, and to achieve strong and sustained target engagement in peripheral blood. The chemical structure is C28H34N10O2 with a molecular weight of 542.64. BIIB091 is an important tool for research into B-cell and myeloid cell-driven autoimmune pathologies. It is not approved for general clinical use and is intended for research purposes. The compound is also known by the catalog number V41446.
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| Molecular Formula |
C28H34N10O2
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| Molecular Weight |
542.64
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| Exact Mass |
542.286
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| CAS # |
2247614-80-6
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| PubChem CID |
135355941
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
1.5
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
40
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| Complexity |
869
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| Defined Atom Stereocenter Count |
1
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| SMILES |
N1(C(C)(C)C)C=C(C(N[C@H]2C3=CC=C(C4C=CN=C(NC5=CN(C)N=C5)N=4)C=C3CN(C3COC3)CC2)=O)N=N1
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| InChi Key |
JSAQBOQCZJHWMA-XMMPIXPASA-N
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| InChi Code |
InChI=1S/C28H34N10O2/c1-28(2,3)38-15-25(34-35-38)26(39)32-24-8-10-37(21-16-40-17-21)13-19-11-18(5-6-22(19)24)23-7-9-29-27(33-23)31-20-12-30-36(4)14-20/h5-7,9,11-12,14-15,21,24H,8,10,13,16-17H2,1-4H3,(H,32,39)(H,29,31,33)/t24-/m1/s1
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| Chemical Name |
1-tert-butyl-N-[(5R)-8-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-2-(oxetan-3-yl)-1,3,4,5-tetrahydro-2-benzazepin-5-yl]triazole-4-carboxamide
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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 : ~125 mg/mL (~230.36 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.83 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. Solubility in Formulation 2: ≥ 2.08 mg/mL (3.83 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8428 mL | 9.2142 mL | 18.4284 mL | |
| 5 mM | 0.3686 mL | 1.8428 mL | 3.6857 mL | |
| 10 mM | 0.1843 mL | 0.9214 mL | 1.8428 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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