BMS-986142

製品コードS8381 バッチS838101

印刷

化学情報

Chemical Structure Synonyms N/A Storage
(From the date of receipt)		 3 years -20°C powder
化学式

C32H30F2N4O4
分子量 572.60 CAS No. 1643368-58-4
Solubility (25°C)* 体外 DMSO 100 mg/mL (174.64 mM)
Water Insoluble
Ethanol Insoluble
体内 （毎回新しく調製した物を用意してください）
Homogeneous suspension
CMC-NA
≥5mg/ml Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

溶剤液（一定の濃度）を調合する

生物活性

製品説明 BMS-986142 is a potent and highly selective reversible small molecule inhibitor of BTK with an IC50 of 0.5 nM. In a panel of 384 kinases, only five kinases were inhibited by BMS-986142 with less than 100-fold selectivity for BTK (TEC, ITK, BLK, TXK and BMX).
in vitro

In B cells stimulated through the B cell receptor (BCR), BMS-986142 potently inhibits signaling and functional end points, including calcium flux (IC50 = 9 nM), production of cytokines, proliferation, and surface expression of the costimulatory molecule CD86 (IC50 = 3−4 nM). In T cells, ITK-catalyzed phosphorylation of PLCγ1 stimulated through the T cell receptor (TCR) is at least 45-fold less potently inhibited by this compound than BTK-dependent signaling end points in B cells, as expected based on the 30-fold selectivity for BTK over ITK in the enzymatic assays[2].
in vivo

In multispecies pharmacokinetic studies, the absolute oral bioavailability of BMS-986142 is 93% in mice, 67% in rats, 33% in cynomolgus monkeys, and 100% in dogs. The total body plasma clearance of this compound is low in all species. The large steady-state volume of distribution observed is indicative of extravascular distribution, in spite of the high protein binding. However, brain penetration is very low in rats (<5% of plasma concentration). This compound blocks the increase in severe proteinuria in a female NZB/W lupus-prone mouse model in vivo. Treatment with this chemical provides robust protection against tubulo-interstitial and glomerular nephritis, as well as inflammatory infiltration[2].

プロトコル(参考用のみ)

キナーゼアッセイ Human Recombinant BTK Enzyme Assay
To V-bottom 384-well plates were added test compounds, human recombinant BTK (1 nM), fluoresceinated peptide (1.5 μM), ATP (20 μM), 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), with a final volume of 30 μL. After incubating at room temperature for 60 min, the reaction was terminated by adding 45 μL of 35 mM EDTA to each sample. The reaction mixture was analyzed by electrophoretic separation of the fluorescent substrate and phosphorylated product. Inhibition data were calculated by comparison to control reactions with no enzyme (for 100% inhibition) and controls with no inhibitor (for 0% inhibition). Dose−response curves were generated to determine the concentration required for inhibiting 50% of BTK activity (IC50). This compound was dissolved at 10 mM in DMSO and evaluated at 11 concentrations.
細胞アッセイ 細胞株 Ramos B cells
濃度 0.4, 1.6, 6, 25, 100 and 400 nM
反応時間 1 h
実験の流れ

B-cell receptor (BCR)-stimulated phospholipase C (PLC)-γ2 phosphorylation in Ramos B cells: After 1 hour of pre-incubation of Ramos B cells in media containing 10% fetal bovine serum (FBS) with varying concentrations of this compound at 37°C, the cells are stimulated with AffiniPure F(ab’)2 fragment goat anti-human immunoglobulin (Ig)M at 50 μg/mL for exactly 2 minutes at 37°C, followed by addition of ice-cold phosphate-buffered saline for quenching. The cells are pelleted and lysed, and PLCγ2 levels are measured by immunoblot using rabbit anti-human phosphoY759-PLCγ2 and analyzed using the Odyssey Infrared Imaging System with normalization to an actin control to ensure consistent loading.
動物実験 動物モデル female NZB/W lupus-prone mouse model
投薬量 30 mg/kg
投与方法 by oral gavage

参考

  • https://pubmed.ncbi.nlm.nih.gov/28742141/
  • https://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.6b01088

Selleckの高級品が、幾つかの出版された研究調査結果（以下を含む）で使われた：

IRAK4 inhibition: an effective strategy for immunomodulating peri-implant osseointegration via reciprocally-shifted polarization in the monocyte-macrophage lineage cells [ BMC Oral Health, 2023, 23(1):265] PubMed: 37158847

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人間や獣医の診断であるか治療的な使用のためにでない。

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