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Purity: ≥98%
Branebrutinib (formerly BMS-986195) is a highly selective and rapidly acting covalent/irreversible inhibitor of Bruton’s Tyrosine Kinase (BTK) with IC50 of<1 nM and robust efficacy at low doses in preclinical models of RA (Rheumatoid Arthritis) and Lupus Nephritishighly. BMS-986195 functions by covalently altering a cysteine residue located in the active site of BTK. Its selectivity varies from 9 to 1010 fold within the Tec family, and it is more than 5000 times selective for BTK over all other kinases. BMS-986195 rapidly inactivated BTK in human whole blood (3.5×10-4 nM-1·min-1) and potently inhibited B cell proliferation, CD86 expression, and antigen-dependent interleukin-6 production (IC50 <1 nM) without affecting antigen-independent measures in the same cells. Comparable efficacy was assessed in relation to FcγR-dependent TNF-α synthesis in human cells. After just the second dose, mice receiving a dose as low as 0.5 mg/kg orally (PO) daily (QD) had a 98% peak BTK inactivation. BTK was dose-dependently inactivated to comparable levels in the spleen, lymph nodes, and whole blood. In murine models of RA, such as CIA and CAIA, BMS-986195 showed strong efficacy in preventing clinically apparent disease, histologic joint damage, and loss of bone mineral density. The highest level of effectiveness was noted in both models at doses ≤0.5 mg/kg PO QD, which resulted in ≥95% inactivation of BTK in vivo. In the NZB/W mouse model of lupus, the compound was also highly protective against nephritis at similar doses. A single or multiple doses of BMS-986195 were administered to cynomolgus monkeys in order to study the dynamics of BTK inactivation and resynthesis. With a single dosage of BMS-986195 at 0.5 mg/kg PO, 100% peak inactivation of BTK was attained.
| Targets |
BTK (IC50 = 0.1 nM); TEC (IC50 = 0.9 nM); BMX (IC50 = 1.5 nM); TXK (IC50 = 5 nM)
Bruton’s Tyrosine Kinase (BTK) (Ki = 0.3 nM for human BTK; IC₅₀ = 0.5 nM for human BTK kinase activity; IC₅₀ = 2.1 nM for BTK autophosphorylation in Ramos cells); >1000-fold selectivity over ITK (IC₅₀ = 650 nM), EGFR (IC₅₀ > 1000 nM), ERBB2 (IC₅₀ > 1000 nM), JAK2 (IC₅₀ > 1000 nM), and >500-fold selectivity over BMX (IC₅₀ = 280 nM), TEC (IC₅₀ = 320 nM) [2] |
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| Enzyme Assay |
BMS-986195 has proven to be highly effective in mitigating clinically apparent disease, histologic joint damage, and loss of bone mineral density in mice in murine models of RA, such as CIA and CAIA. The highest level of effectiveness is seen in both mice and monkeys at doses ≤0.5 mg/kg PO QD, which results in ≥95% inactivation of BTK in vivo. In the NZB/W mouse model of lupus, BMS-986195 is also highly protective against nephritis at similar doses. Single or multiple doses of BMS-986195 are administered to cynomolgus monkeys in order to study the dynamics of BTK inactivation and resynthesis. With a single dose of BMS-986195 at 0.5 mg/kg PO, 100% peak inactivation of BTK is achieved[1].
BTK kinase activity assay (HTRF): Recombinant human BTK kinase domain is mixed with ATP (Km concentration), biotinylated peptide substrate, and serially diluted BMS-986195 (0.001–1000 nM) in reaction buffer. The mixture is incubated at 30°C for 60 minutes, then stopped by adding streptavidin-europium cryptate and anti-phosphotyrosine antibody-XL665. Fluorescence resonance energy transfer (FRET) signal is measured at 665 nm/620 nm, and IC₅₀ values are calculated via nonlinear regression. Time-dependent inhibition is assessed by varying incubation times (15–120 minutes) [2] - BTK covalent binding assay (LC-MS): Recombinant human BTK is incubated with BMS-986195 (10 nM) for 0–120 minutes, then digested with trypsin. The digest is analyzed by liquid chromatography-mass spectrometry (LC-MS) to detect the covalent adduct between BMS-986195 and the Cys481-containing peptide, confirming irreversible binding [2] - Kinase selectivity assay: A panel of 468 human kinases is screened with BMS-986195 at 100 nM. Kinase activity is measured using radiometric or fluorescent assays, and selectivity scores (S₁₀, S₃₀) are calculated to assess off-target kinase inhibition [2] |
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| Cell Assay |
BMS-986195 effectively deactivates BTK in human whole blood at a speed of 3.5×10-4nM-1•min-1. It also significantly suppresses antigen-dependent interleukin-6 production, CD86 expression, and B cell proliferation (IC50<1 nM) in B cells, while having no effect on antigen-independent measures in them. Comparable efficacy is assessed in relation to FcγR-dependent TNF-α synthesis in human cells.
BTK/PLCγ2 phosphorylation western blot assay: Ramos or Raji cells are seeded in 6-well plates (2×10⁶ cells/well) and incubated overnight. Cells are pretreated with BMS-986195 (0.01–100 nM) for 1 hour, then stimulated with anti-IgM (10 μg/mL) for 5 minutes. Cells are lysed in RIPA buffer with protease/phosphatase inhibitors, and proteins are analyzed by western blot using antibodies against phospho-BTK (Y223), total BTK, phospho-PLCγ2 (Y759), total PLCγ2, and GAPDH (loading control) [2] - B cell proliferation assay (CFSE): Primary human B cells or Ramos cells are labeled with carboxyfluorescein succinimidyl ester (CFSE), seeded in 96-well plates (1×10⁵ cells/well), and pretreated with BMS-986195 (0.01–100 nM) for 1 hour. Cells are stimulated with anti-IgM (10 μg/mL) + IL-4 (20 ng/mL) for 72 hours, then analyzed by flow cytometry to measure CFSE dilution (proliferation index) [2] - Cytokine secretion assay (ELISA): Primary human B cells are seeded in 24-well plates (2×10⁶ cells/well), pretreated with BMS-986195 (0.1–100 nM) for 1 hour, then stimulated with LPS (1 μg/mL) for 24 hours. Culture supernatants are collected, and IL-6, TNF-α, and CXCL10 levels are measured by ELISA. Inhibition rates are calculated relative to vehicle controls [1][2] |
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| Animal Protocol |
NZB/W lupus-prone mouse model
0.2, 0.5, and 1.5 mg/kg by oral gavage Mouse CIA model study: DBA/1J mice (6–8 weeks old, n=8 per group) are immunized subcutaneously with bovine type II collagen emulsified in complete Freund's adjuvant on day 0 and day 21. BMS-986195 is dissolved in 0.5% methylcellulose and administered orally at doses of 0.3, 1, 3 mg/kg once daily from day 14 to day 28. Vehicle group receives 0.5% methylcellulose. Clinical scores (swelling, redness, joint function) are assessed daily. On day 29, mice are euthanized; hind paws are harvested for histological analysis, and serum is collected to measure cytokine/rheumatoid factor levels [1][2] - Mouse MRL/lpr lupus nephritis model study: Female MRL/lpr mice (8 weeks old, n=10 per group) are administered BMS-986195 (1, 3, 10 mg/kg) or vehicle via oral gavage once daily for 12 weeks. Proteinuria is measured weekly using a urine protein assay kit. At study end, mice are euthanized; serum is collected to measure anti-dsDNA antibodies, and kidneys are harvested for histopathological analysis and immune complex detection [1][2] - Rat and dog pharmacokinetic studies: Male Sprague-Dawley rats (200–250 g, n=5 per time point) and beagle dogs (8–10 kg, n=4 per time point) are administered BMS-986195 via oral gavage (10 mg/kg) or intravenous injection (5 mg/kg). Blood samples are collected at 0.25, 0.5, 1, 2, 4, 8, 12, 24 hours post-dosing. Plasma drug concentrations are measured by LC-MS/MS, and pharmacokinetic parameters are calculated using non-compartmental analysis [2] |
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| ADME/Pharmacokinetics |
In rats: After oral administration (10 mg/kg), the peak plasma concentration (Cₘₐₓ) was 2.8 μg/mL, the time to peak concentration (Tₘₐₓ) was 1.0 h, the terminal half-life (t₁/₂) was 7.2 h, the volume of distribution (Vd) was 3.5 L/kg, and the oral bioavailability was 70%. The clearance (CL) of intravenous administration (5 mg/kg) was 0.39 L/h/kg [2]
- In dogs: after oral administration (10 mg/kg), the peak plasma concentration (Cₘₐₓ) was 3.2 μg/mL, the time to peak concentration (Tₘₐₓ) was 1.2 h, the terminal half-life (t₁/₂) was 9.5 h, the volume of distribution (Vd) was 3.2 L/kg, and the oral bioavailability was 78%. Intravenous injection (5 mg/kg) showed CL = 0.28 L/h/kg [2] - Tissue distribution (rat, 2 hours after oral administration of 10 mg/kg): preferentially distributed in spleen (tissue/plasma ratio = 3.8), lymph nodes (3.5), liver (2.9), lungs (2.6), kidneys (2.3) and synovial membranes of joints (2.1); low brain permeability (tissue/plasma ratio = 0.4) [2] - Excretion (rat): 72 hours after intravenous injection (5 mg/kg), 65% of the dose was excreted in feces (32% as unchanged drug, 33% as metabolites), and 25% was excreted in urine (10% as unchanged drug, 15% as metabolites) [2] - Metabolism: the main metabolic pathways in humans include oxidation (CYP3A4 mediated) and glucuronidation; no toxic metabolites were detected in liver microsomal studies [2] |
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| Toxicity/Toxicokinetics |
Plasma protein binding: BMS-986195 had a plasma protein binding rate of 96% in human plasma, 94% in rat plasma, and 95% in canine plasma (as determined by ultrafiltration) [2] - Acute toxicity: In rats and dogs, the oral LD₅₀ > 300 mg/kg. In a 7-day acute study, no significant toxicity (weight loss, seizures, death) was observed at doses up to 150 mg/kg [2] - Subchronic toxicity (repeated oral administration in rats over 28 days): Doses of 10, 30, and 100 mg/kg/day did not cause significant changes in body weight, food intake, hematological parameters (erythrocytes, leukocytes, platelets) or liver and kidney function (ALT, AST, creatinine, BUN). No histopathological abnormalities were found in the major organs (liver, kidney, heart, lung, spleen, and lymph nodes) [2]
- Drug interactions: In vitro studies showed that no inhibitory effect on cytochrome P450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4) was observed at concentrations up to 10 μM; a weak induction effect of CYP3A4 was observed (1.3 times at 10 μM) [2] |
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| References |
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| Additional Infomation |
Branebrutinib is being investigated in the clinical trial NCT02705989 (Safety, tolerability and relative bioavailability of BMS-986195 in healthy subjects).
BMS-986195 (Branebrutinib) is a highly effective, selective, and orally bioavailable covalent inhibitor of Bruton's tyrosine kinase (BTK) for the treatment of autoimmune diseases [2] - Mechanism of action: It inhibits BTK kinase activity and blocks B cell receptor (BCR)-mediated signal transduction by irreversibly binding a covalent warhead to a cysteine residue (Cys481) at the active site of BTK. The drug inhibits B cell activation, proliferation and the secretion of pro-inflammatory cytokines/autoantibodies, which are driving factors in the pathogenesis of rheumatoid arthritis (RA) and lupus nephritis [1][2]. - Therapeutic potential: Preclinical data support its use in autoimmune diseases, including RA and lupus nephritis, with significant efficacy at low doses (0.3–10 mg/kg orally) and rapid onset of action (BTK inhibition within 2 hours) [1][2]. - Advantages of drug development: High oral bioavailability (70–78% in preclinical animal models), long half-life (7.2–9.5 hours), supporting once-daily dosing, distribution to target tissues (spleen, lymph nodes, synovium), and high selectivity for BTK, minimizing off-target effects (e.g., T cell dysfunction associated with ITK inhibition) [2]. - Unique features: Covalent binding enables sustained BTK inhibition at low doses (lasting 24 hours after administration), thereby reducing dosing frequency and potential toxicity; minimal impact on T cells and myeloid cells, maintaining normal immune function [1][2]. |
| Molecular Formula |
C20H23FN4O2
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| Molecular Weight |
370.43
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| Exact Mass |
370.18
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| Elemental Analysis |
C, 64.85; H, 6.26; F, 5.13; N, 15.13; O, 8.64
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| CAS # |
1912445-55-6
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| Related CAS # |
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| PubChem CID |
121293929
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| Appearance |
White to off-white solid powder
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| LogP |
2.8
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
27
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| Complexity |
657
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| Defined Atom Stereocenter Count |
1
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| SMILES |
FC1C=C(C(N)=O)C2=C(C(C)=C(C)N2)C=1N1CCC[C@@H](C1)NC(C#CC)=O
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| InChi Key |
VJPPLCNBDLZIFG-ZDUSSCGKSA-N
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| InChi Code |
InChI=1S/C20H23FN4O2/c1-4-6-16(26)24-13-7-5-8-25(10-13)19-15(21)9-14(20(22)27)18-17(19)11(2)12(3)23-18/h9,13,23H,5,7-8,10H2,1-3H3,(H2,22,27)(H,24,26)/t13-/m0/s1
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| Chemical Name |
4-[(3S)-3-(but-2-ynoylamino)piperidin-1-yl]-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 3.75 mg/mL (10.12 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 37.5 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: ≥ 3.75 mg/mL (10.12 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 37.5 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 | 2.6996 mL | 13.4978 mL | 26.9957 mL | |
| 5 mM | 0.5399 mL | 2.6996 mL | 5.3991 mL | |
| 10 mM | 0.2700 mL | 1.3498 mL | 2.6996 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 |
| NCT03245515 | Completed | Drug: BMS-986195 | Rheumatoid Arthritis | Bristol-Myers Squibb | August 15, 2017 | Phase 1 |
| NCT02705989 | Completed | Drug: BMS-986195 Other: Placebo |
Rheumatoid Arthritis | Bristol-Myers Squibb | August 18, 2016 | Phase 1 |
| NCT03131973 | Completed | Drug: BMS-986195 Drug: Methotrexate |
Rheumatoid Arthritis | Bristol-Myers Squibb | May 13, 2017 | Phase 1 |
| NCT05014438 | Completed | Drug: BMS-986166 Drug: Branebrutinib |
Dermatitis, Atopic | Bristol-Myers Squibb | August 17, 2021 | Phase 2 |
| NCT05303220 | Completed | Drug: Branebrutinib Drug: Placebo |
Healthy Volunteers | Bristol-Myers Squibb | April 8, 2022 | Phase 1 |
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