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BMS-935177 Sale

目录号 : GC31760

BMS-935177 is a potent, reversible Bruton's Tyrosine Kinase (BTK) inhibitor with an IC50 value of 2.8 nM and demonstrates good kinase selectivity. It is more potent against BTK than other kinase, including the other Tec family kinases (TEC, BMX, ITK, and TXK) over which the compound is between 5- and 67-fold selective.

BMS-935177 Chemical Structure

Cas No.:1231889-53-4

规格 价格 库存 购买数量
10mM (in 1mL DMSO)
¥2,170.00
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2mg
¥982.00
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5mg
¥1,964.00
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10mg
¥3,124.00
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25mg
¥6,426.00
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50mg
¥11,156.00
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100mg
¥18,743.00
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Sample solution is provided at 25 µL, 10mM.

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Quality Control & SDS

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实验参考方法

Kinase experiment:

BMS-935177 is dissolved at 10 mM in DMSO and evaluated at 11 concentrations . To V-bottom 384- well plates are added BMS-935177, human recombinant BTK (1 nM), fluoresceinated peptide (1.5 μM), ATP (20 μM (Km app)), and assay buffer (20 mM HEPES, pH 7.4, 10 mM MgCl2, 0.015% Brij 35 surfactant, and 4 mM DTT in 1.6% DMSO), with a final volume of 30 μL. After incubation at room temperature for 60 min, the reaction is terminated by adding 45 μL of 35 mM EDTA to each sample. The reaction mixture is analyzed on the by electrophoretic separation of the fluorescent substrate and phosphorylated product (excitation, 488 nm; emission, 530 nm)[1].

Animal experiment:

Rats[1]Male Sprague−Dawley rats (255-298 g) are used in the PK studies. To investigate the oral bioavailability of BMS-935177 after crystalline microsuspension doses, rats receive BMS-935177 by oral gavage (1, 5, and 20 mg/kg), T99.5% 10 mM citrate buffer, pH 4, 0.02% DOSS, Methocel A4M. Serial blood samples are obtained after oral dosing at 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, and 24 h postdose. Plasma samples, obtained by centrifugation at 4 °C (1500-2000g), are stored at −20 °C until analysis[1].Mice[1]Efficacy of BMS-935177 (10 and 30 mg/kg) vs vehicle and dexamethasone (Dex) is studied in a mouse anti-collagen antibody-induced arthritis (CAIA) inflammation model. Mice are injected intraperitoneally (ip) with a mixture of four monoclonal antimouse type II collagen antibodies (1 mg of each). Daily oral dosing is immediately started with vehicle (EtOH:TPGS:PEG300, 5:5:90), BMS-935177 (10 or 30 mg/kg), or dexamethasone (dex, 1 mg/kg). Three days later, the mice are injected ip with 1.25 mg/kg LPS. Thereafter, mice are monitored 3×/ week for the development and severity of paw inflammation[1].

References:

[1]. De Lucca GV, et al. Small Molecule Reversible Inhibitors of Bruton's Tyrosine Kinase (BTK): Structure-Activity Relationships Leading to the Identification of 7-(2-Hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide (BMS-935177). J Med Chem. 2016 Sep 8;59(17):7915-35.

产品描述

BMS-935177 is a potent, reversible Bruton's Tyrosine Kinase (BTK) inhibitor with an IC50 value of 2.8 nM and demonstrates good kinase selectivity. It is more potent against BTK than other kinase, including the other Tec family kinases (TEC, BMX, ITK, and TXK) over which the compound is between 5- and 67-fold selective.

BMS-935177 shows greater than 50-fold selectivity over the SRC family of kinases, including 1100-fold selectivity over SRC itself. Other kinases inhibited with a potency less than 150 nM (50-fold selectivity) included TRKA, HER4, TRKB, and RET. It inhibits calcium flux in human Ramos B cells (IC50 = 27 nM) and inhibits CD69 surface expression in peripheral B cells stimulated with anti-IgM and anti-IgG. However, BMS-935177 has no effect on CD69 surface expression in B cells stimulated through the CD40 receptor with CD40 ligand. Against IgG-containing immune complex-driven low affinity activating Fcγ receptor (FcγRIIa and FcγRIII) end points in peripheral blood mononuclear cells (PBMCs), BMS-935177 effectively inhibited TNFα production with an IC50 value of 14 nM[1].

Plasma protein binding for BMS-935177 is high for all species, with less than 1% free for human. It has excellent oral bioavailability in all preclinical species, from both suspension and solution dosing, despite its low aqueous solubility. The oral bioavailability for BMS-935177 with solution dosing ranges from 84% to 100% in rat, mouse, dog, and cynomolgus monkey, with low clearance in single intravenous (iv) infusion studies. When dosed at 2 mg/kg i.v. in mouse and rat, the T1/2 of BMS-935177 is 4 h and 5.1 h respectively[1].

[1] De Lucca GV, et al. J Med Chem. 2016, 59(17):7915-35.

Chemical Properties

Cas No. 1231889-53-4 SDF
Canonical SMILES O=C(C1=CC=C(C2=CC=CC(N3C=NC4=C(C=CC=C4)C3=O)=C2C)C5=C1NC6=C5C=CC(C(C)(O)C)=C6)N
分子式 C31H26N4O3 分子量 502.56
溶解度 DMSO : ≥ 130 mg/mL (258.68 mM) 储存条件 Store at -20°C
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溶解性数据

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1 mg 5 mg 10 mg
1 mM 1.9898 mL 9.9491 mL 19.8981 mL
5 mM 0.398 mL 1.9898 mL 3.9796 mL
10 mM 0.199 mL 0.9949 mL 1.9898 mL
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Research Update

Small Molecule Reversible Inhibitors of Bruton's Tyrosine Kinase (BTK): Structure-Activity Relationships Leading to the Identification of 7-(2-Hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide (BMS-935177)

Bruton's tyrosine kinase (BTK) belongs to the TEC family of nonreceptor tyrosine kinases and plays a critical role in multiple cell types responsible for numerous autoimmune diseases. This article will detail the structure-activity relationships (SARs) leading to a novel second generation series of potent and selective reversible carbazole inhibitors of BTK. With an excellent pharmacokinetic profile as well as demonstrated in vivo activity and an acceptable safety profile, 7-(2-hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide 6 (BMS-935177) was selected to advance into clinical development.

Assessment of the effects of Syk and BTK inhibitors on GPVI-mediated platelet signaling and function

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.