| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 25mg |
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| 50mg |
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| 100mg |
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| 250mg |
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| 500mg |
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| Other Sizes |
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| Targets |
BTK (IC50 = 0.5 nM); TEC (IC50 = 10 nM); ITK (IC50 = 15 nM); BLK (IC50 = 23 nM); TXK (IC50 = 28 nM); BMX (IC50 = 32 nM); LCK (IC50 = 71 nM); SRC (IC50 = 1100 nM)
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| ln Vitro |
BMS-986142 potently inhibits human recombinant BTK with an IC50 of 0.5 nM in enzymatic assays. BMS-986142 exhibits high selectivity against a panel of 384 kinases; only five other kinases (Tec, ITK, BLK, Txk, and BMX) are inhibited with selectivity for BTK that is less than 100 times. Out of these kinases, only Tec (IC50=10 nM) is inhibited with a selectivity that is less than thirty times when compared to BTK. These four kinases are members of the Tec family of kinases. BMS-986142 does not prevent peripheral blood B cells from expressing CD86 or CD69 when stimulated by CD40L (IC50>10,000 nM for both). With an IC50 of 9 nM, BMS-986142 inhibits BTK-dependent calcium flux in response to anti-IgM treatment of Ramos B cells, activating BCR[2].
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| ln Vivo |
BMS-986142 at 4, 10, and 30 mg/kg causes dose-dependent reductions in clinically evident disease of 26%, 43%, and 79%, respectively at the end of the study. It's interesting to note that when administered in addition to MTX, 4 mg/kg BMS-986142 offers an additive benefit in clinical scores (54% inhibition) as opposed to 19% inhibition with MTX alone. In comparison to 24% and 10%, respectively, with either medication alone, co-administration of BMS-986142 at 4 mg/kg with MTX results in a 53% reduction in inflammation and bone resorption. Moreover, 10 and 30 mg/kg BMS-986142 significantly inhibit serum anti-collagen II IgG titers. If BMS-986142 is not administered until day 21, the collagen booster, there are also dose-dependent reductions in clinical scores. At the conclusion of the trial, BMS-986142 doses of 2, 4, and 25 mg/kg produce clinical score reductions of 17%, 37%, and 67%, respectively[2].
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| Enzyme Assay |
Test compounds, fluoresceinated peptide (1.5 μM), ATP (20 μM), human recombinant BTK (1 nM), and assay buffer (20 mM HEPES at pH 7.4, 10 mM MgCl2, 0.015% Brij 35 surfactant, and 4 mM DTT in 1.6% DMSO) were added to V-bottom 384-well plates, with a final volume of 30 μL. 45 μL of 35 mM EDTA was added to each sample to stop the reaction after it had been incubated for 60 minutes at room temperature. The fluorescent substrate and phosphorylated product were separated electrophoretically to analyze the reaction mixture. By comparing the inhibition data to both controls without an inhibitor (for 0% inhibition) and controls with no enzyme (for 100% inhibition), the inhibition levels were computed. The concentration needed to inhibit 50% of BTK activity (IC50) was found by creating dose-response curves. In DMSO, compounds were dissolved at a concentration of 10 mM and assessed at 11 concentrations.
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| Cell Assay |
Ramos B cells phosphorylate phospholipase C (PLC)-γ2 in response to stimulation from the B-cell receptor (BCR): After pre-incubating Ramos B cells for one hour at 37°C in media containing 10% fetal bovine serum (FBS) with different concentrations of BMS-986142, the cells are stimulated for precisely two minutes at 37°C with AffiniPure F(ab')2 fragment goat anti-human immunoglobulin (Ig)M at 50 μg/mL. Ice-cold phosphate-buffered saline is then added to quench the cells. After the cells are lysed and pelleted, the levels of PLCγ2 are determined by immunoblotting with rabbit anti-human phosphoY759-PLCγ2, and the Odyssey Infrared Imaging System is used to analyze the results. To guarantee uniform loading, actin control is normalized.
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| Animal Protocol |
Mice: In male DBA/1 mice, 200 μg of admixed bovine type II collagen is injected subcutaneously at the base of the tail. Similar stimulation is given to the mice 21 days later. BMS-986142 in EtOH: TPGS: PEG300 (5:5:90) is used to initiate PO QD dosing for preventative administration right away; however, for therapeutic administration, dosing is postponed until day 21 of the booster immunization. In mice used for BMS-986142 plus MTX preventative studies, the doses are as follows: vehicle; 4, 10, or 30 mg/kg of BMS-986142; 4 mg/kg of BMS-986142 plus MTX 0.25 mg/kg; or MTX at 0.25 mg/kg per day. Mice are given vehicle daily, BMS-986142 at 2, 4, or 25 mg/kg daily, BMS-986142 at 2 or 4 mg/kg daily plus etanercept at 15 mg/kg IP twice weekly (BIW), or etanercept at 15 mg/kg IP BIW for therapeutic studies involving BMS-986142 plus etanercept. Mice are given vehicle daily, BMS-986142 at 10 or 30 mg/kg daily, murine CTLA-4-Ig at 0.05 or 0.2 mg/kg IP BIW, or BMS-986142 at 10 mg/kg daily plus murine CTLA-4-Ig at 0.05 or 0.2 mg/kg IP BIW for the preventative studies involving BMS-986142 plus murine cytotoxic T lymphocyte-associated protein 4 immunoglobulin (CTLA-4-Ig). Dosing is done starting on day 0 and continuing for the full 36-day study [2].
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| References |
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| Molecular Formula |
C32H30F2N4O4
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|---|---|---|
| Molecular Weight |
572.61
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| Exact Mass |
572.22
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| Elemental Analysis |
C, 67.12; H, 5.28; F, 6.64; N, 9.78; O, 11.18
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| CAS # |
1643368-58-4
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| Related CAS # |
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| Appearance |
Solid powder
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| SMILES |
CC1=C(C=CC=C1N2C(=O)C3=C(C(=CC=C3)F)N(C2=O)C)C4=C(C=C(C5=C4C6=C(N5)C[C@H](CC6)C(C)(C)O)C(=O)N)F
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| InChi Key |
ZRYMMWAJAFUANM-INIZCTEOSA-N
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| InChi Code |
InChI=1S/C32H30F2N4O4/c1-15-17(7-6-10-24(15)38-30(40)19-8-5-9-21(33)28(19)37(4)31(38)41)25-22(34)14-20(29(35)39)27-26(25)18-12-11-16(32(2,3)42)13-23(18)36-27/h5-10,14,16,36,42H,11-13H2,1-4H3,(H2,35,39)/t16-/m0/s1
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| Chemical Name |
(7S)-3-fluoro-4-[3-(8-fluoro-1-methyl-2,4-dioxoquinazolin-3-yl)-2-methylphenyl]-7-(2-hydroxypropan-2-yl)-6,7,8,9-tetrahydro-5H-carbazole-1-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: ≥ 2.08 mg/mL (3.63 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. Solubility in Formulation 2: 2.08 mg/mL (3.63 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. 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. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (3.63 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7464 mL | 8.7319 mL | 17.4639 mL | |
| 5 mM | 0.3493 mL | 1.7464 mL | 3.4928 mL | |
| 10 mM | 0.1746 mL | 0.8732 mL | 1.7464 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 |
| NCT02257151 | Completed | Drug: BMS-986142 Drug: Placebo |
Healthy Adult | Bristol-Myers Squibb | September 2014 | Phase 1 |
| NCT02880670 | Completed | Drug: BMS-986142 | Arthritis | Bristol-Myers Squibb | August 2016 | Phase 1 |
| NCT02832180 | Completed | Drug: OC containing EE and NET Drug: BMS-986142 |
Arthritis | Bristol-Myers Squibb | May 2016 | Phase 1 |
| NCT02762123 | Completed | Drug: BMS-986142 200mg Drug: BMS-986142 350mg |
Rheumatoid Arthritis | Bristol-Myers Squibb | May 2016 | Phase 1 |
| NCT02638948 | Completed | Drug: BMS-986142 Drug: Placebo |
Rheumatoid Arthritis | Bristol-Myers Squibb | February 16, 2016 | Phase 2 |
BMS-986142 inhibits RANK-L-induced osteoclastogenesis in human monocytic precursors.PLoS One.2017 Jul 24;12(7):e0181782. |
BMS-986142 blocks neoantigen-induced antibody responses.PLoS One.2017 Jul 24;12(7):e0181782. |
BMS-986142 is efficacious against CIA in mice.PLoS One.2017 Jul 24;12(7):e0181782. |
Therapeutic treatment with BMS-986142 co-administered with etanercept protected from CIA in mice.PLoS One.2017 Jul 24;12(7):e0181782. |
BMS-986142 co-administered with CTLA-4-Ig shows an enhanced effect against CIA in mice.
Inhibition of anti-IgM-stimulated phosphorylation of phospholipase C-γ2 in Ramos B cells by BMS-986142.PLoS One.2017 Jul 24;12(7):e0181782. |
BMS-986142 is efficacious in the murine CAIA model.PLoS One.2017 Jul 24;12(7):e0181782. |
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