BMS-986195
(Synonyms: BMS-986195) 目录号 : GC32844
A covalent BTK inhibitor
Cas No.:1912445-55-6
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Branebrutinib is a covalent inhibitor of Bruton’s tyrosine kinase (BTK; IC50 = 0.1 nM).1 It is greater than 5,000-fold selective for BTK over a panel of 240 kinases but does inhibit the additional Tec family kinases Tec, BMX, and TMX (IC50s = 0.9, 1.5, and 5 nM, respectively). Branebrutinib inhibits calcium flux in Ramos B cells induced by B cell receptor (BCR) stimulation (IC50 = 7.2 nM), as well as BCR stimulation-induced proliferation of, and CD86 surface expression in, peripheral B cells (IC50s = 0.04 and 0.3 nM, respectively). It inhibits TNF-α production in human peripheral blood mononuclear cells (PMBCs) induced by Fcγ receptor stimulation (IC50 = 0.3 nM). Branebrutinib (0.5 mg/kg) is completely protective against bone destruction in a mouse model of collagen-induced arthritis. It also reduces proteinuria and glomerular IgG immune complex deposition and increases survival in an NZB/W lupus-prone mouse model.
1.Watterson, S.H., Liu, Q., Bertrand, M.B., et al.Discovery of branebrutinib (BMS-986195): A strategy for identifying a highly potent and selective covalent inhibitor providing rapid in vivo inactivation of Bruton's tyrosine kinase (BTK)J. Med. Chem.62(7)3228-3250(2019)
| Cas No. | 1912445-55-6 | SDF | |
| 别名 | BMS-986195 | ||
| Canonical SMILES | O=C(C1=CC(F)=C(N2C[C@@H](NC(C#CC)=O)CCC2)C3=C1NC(C)=C3C)N | ||
| 分子式 | C20H23FN4O2 | 分子量 | 370.42 |
| 溶解度 | DMSO : ≥ 100 mg/mL (269.96 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.6996 mL | 13.4982 mL | 26.9964 mL |
| 5 mM | 0.5399 mL | 2.6996 mL | 5.3993 mL |
| 10 mM | 0.27 mL | 1.3498 mL | 2.6996 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Branebrutinib (BMS-986195), a Bruton's Tyrosine Kinase Inhibitor, Resensitizes P-Glycoprotein-Overexpressing Multidrug-Resistant Cancer Cells to Chemotherapeutic Agents
Front Cell Dev Biol 2021 Jul 19;9:699571.PMID:34350184DOI:10.3389/fcell.2021.699571.
The overexpression of P-glycoprotein (P-gp/ABCB1), an ATP-binding cassette (ABC) drug transporter, often contributes to the development of multidrug resistance (MDR) in cancer cells. P-gp mediates the ATP hydrolysis-dependent efflux of a wide range of chemotherapeutic agents out of cancer cells, thereby reducing the intracellular drug accumulation and decreasing the chemosensitivity of these multidrug-resistant cancer cells. Studies with tyrosine kinase inhibitors (TKIs) in P-gp-overexpressing cells have shown that certain TKIs could reverse MDR mediated by P-gp, while some TKIs are transported by P-gp. In the present work, we explored the prospect of repositioning branebrutinib (BMS-986195), a highly selective inhibitor of Bruton's tyrosine kinase (BTK), to resensitize P-gp-overexpressing multidrug-resistant cancer cells to chemotherapeutic agents. Our results demonstrated that branebrutinib is capable of reversing P-gp-mediated MDR at sub-toxic concentrations, most likely by directly inhibiting the drug transport function of P-gp. Our findings were supported by the result of branebrutinib stimulating the ATPase activity of P-gp in a concentration-dependent manner and the in silico study of branebrutinib binding to the substrate-binding pocket of P-gp. In addition, we found that branebrutinib is equally cytotoxic to drug-sensitive parental cell lines and the respective P-gp-overexpressing multidrug-resistant variants, suggesting that it is unlikely that the overexpression of P-gp in cancer cells plays a significant role in reduced susceptibility or resistance to branebrutinib. In summary, we discovered an additional pharmacological action of branebrutinib against the activity of P-gp, which should be investigated further in future drug combination studies.
Discovery of Branebrutinib (BMS-986195): A Strategy for Identifying a Highly Potent and Selective Covalent Inhibitor Providing Rapid in Vivo Inactivation of Bruton's Tyrosine Kinase (BTK)
J Med Chem 2019 Apr 11;62(7):3228-3250.PMID:30893553DOI:10.1021/acs.jmedchem.9b00167.
Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec family of kinases and is essential for B cell receptor (BCR) mediated signaling. BTK also plays a critical role in the downstream signaling pathways for the Fcγ receptor in monocytes, the Fcε receptor in granulocytes, and the RANK receptor in osteoclasts. As a result, pharmacological inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as rheumatoid arthritis and lupus. This article will outline the evolution of our strategy to identify a covalent, irreversible inhibitor of BTK that has the intrinsic potency, selectivity, and pharmacokinetic properties necessary to provide a rapid rate of inactivation systemically following a very low dose. With excellent in vivo efficacy and a very desirable tolerability profile, 5a (branebrutinib, BMS-986195) has advanced into clinical studies.
Safety, pharmacokinetics and pharmacodynamics of branebrutinib (BMS-986195), a covalent, irreversible inhibitor of Bruton's tyrosine kinase: Randomised phase I, placebo-controlled trial in healthy participants
Br J Clin Pharmacol 2020 Sep;86(9):1849-1859.PMID:32198939DOI:10.1111/bcp.14290.
Aims: Branebrutinib (BMS-986195) is a potent, highly selective, oral, small-molecule, covalent inhibitor of Bruton's tyrosine kinase (BTK). This study evaluated safety, pharmacokinetics and pharmacodynamics of branebrutinib in healthy participants. Methods: This double-blind, placebo-controlled, single- and multiple-ascending dose (SAD; MAD) Phase I study (NCT02705989) enrolled participants into 3 parts: SAD, MAD and JMAD (MAD in first-generation Japanese participants). In each part, participants were randomised 3:1 to receive branebrutinib (SAD: 0.3-30 mg; [J]MAD: 0.3-10 mg) or placebo. Participants in the MAD parts received branebrutinib daily for 14 days and were followed for 14 days postdosing. Safety was assessed by monitoring, laboratory and physical examinations, vital signs, and recording adverse events (AEs). Pharmacodynamics were assessed with a mass spectrometry assay that measured drug-occupied and free BTK. Results: The SAD, MAD and JMAD parts of the study included 40, 32 and 24 participants. Branebrutinib was well tolerated and AEs were mild/moderate, except for 1 serious AE that led to discontinuation. Branebrutinib was rapidly absorbed, with maximum plasma concentration occurring within 1 hour and a half-life of 1.2-1.7 hours, dropping to undetectable levels within 24 hours. BTK occupancy was rapid, with 100% occupancy reached after a single 10-mg dose. BTK occupancy decayed predictably over time (mean half-life in MAD panels: 115-154 hours), such that pharmacodynamic effects were maintained after branebrutinib plasma levels fell below the lower limit of quantification. Conclusion: Rapid and high occupancy of BTK and the lack of notable safety findings support further clinical development of branebrutinib.
Assessment of the effects of Syk and BTK inhibitors on GPVI-mediated platelet signaling and function
Am J Physiol Cell Physiol 2021 May 1;320(5):C902-C915.PMID:33689480DOI:10.1152/ajpcell.00296.2020.
Spleen tyrosine kinase (Syk) and Bruton's tyrosine kinase (BTK) play critical roles in platelet physiology, facilitating intracellular immunoreceptor tyrosine-based activation motif (ITAM)-mediated signaling downstream of platelet glycoprotein VI (GPVI) and GPIIb/IIIa receptors. Small molecule tyrosine kinase inhibitors (TKIs) targeting Syk and BTK have been developed as antineoplastic and anti-inflammatory therapeutics and have also gained interest as antiplatelet agents. Here, we investigate the effects of 12 different Syk and BTK inhibitors on GPVI-mediated platelet signaling and function. These inhibitors include four Syk inhibitors, Bay 61-3606, R406 (fostamatinib), entospletinib, TAK-659; four irreversible BTK inhibitors, ibrutinib, acalabrutinib, ONO-4059 (tirabrutinib), AVL-292 (spebrutinib); and four reversible BTK inhibitors, CG-806, BMS-935177, BMS-986195, and fenebrutinib. In vitro, TKIs targeting Syk or BTK reduced platelet adhesion to collagen, dense granule secretion, and alpha granule secretion in response to the GPVI agonist cross-linked collagen-related peptide (CRP-XL). Similarly, these TKIs reduced the percentage of activated integrin αIIbβ3 on the platelet surface in response to CRP-XL, as determined by PAC-1 binding. Although all TKIs tested inhibited phospholipase C γ2 (PLCγ2) phosphorylation following GPVI-mediated activation, other downstream signaling events proximal to phosphoinositide 3-kinase (PI3K) and PKC were differentially affected. In addition, reversible BTK inhibitors had less pronounced effects on GPIIb/IIIa-mediated platelet spreading on fibrinogen and differentially altered the organization of PI3K around microtubules during platelets spreading on fibrinogen. Select TKIs also inhibited platelet aggregate formation on collagen under physiological flow conditions. Together, our results suggest that TKIs targeting Syk or BTK inhibit central platelet functional responses but may differentially affect protein activities and organization in critical systems downstream of Syk and BTK in platelets.
Determination of Real Time in Vivo Drug Receptor Occupancy for a Covalent Binding Drug as a Clinical Pharmacodynamic Biomarker by Immunocapture-LC-MS/MS
Anal Chem 2019 Jul 2;91(13):8443-8452.PMID:31247719DOI:10.1021/acs.analchem.9b01462.
We report a novel immunocapture (IC)-LC-MS/MS methodology to directly measure real time in vivo receptor occupancy (RO) for a covalent binding drug in blood lysate. A small molecule quencher was added immediately after sample collection to convert the free receptor to a quencher-bound receptor (QB-R) which was measured with the drug-bound receptor (DB-R) simultaneously by LC-MS/MS after immunocapture enrichment, followed by trypsin digestion. Addition of the quencher is necessary to prevent the free receptor from ex vivo binding with the drug. The real time RO was calculated based on the concentrations of DB-R and the free receptor (which is now QB-R) that were obtained from each sample. This strategy has been successfully applied to the measurement of the RO for Bruton's tyrosine kinase (BTK) in the blood lysate of monkeys after dosing with branebrutinib (BMS-986195), a covalent BTK inhibitor being evaluated to treat rheumatoid arthritis. A custom-made quencher, which is more reactive to BTK than branebrutinib, was added in excess amount to bind with all available free BTK to form quencher-bound BTK (QB-BTK) during blood sample collection. To measure a wide range of % BTK RO, including those of <5% or >95%, the required LLOQ at 0.125 nM for QB-BTK and 0.250 nM for drug-bound BTK (DB-BTK) in blood lysate were successfully achieved by using this IC-LC-MS/MS strategy. This proof-of-concept assay demonstrated its suitability with high throughput for real time in vivo BTK RO measurement as a pharmacodynamic (PD) biomarker for clinical drug development.