Avagacestat (BMS-708163)

製品コードS1262 バッチS126201

印刷

化学情報

Chemical Structure Synonyms N/A Storage
(From the date of receipt)		 3 years -20°C powder
1 years -80°C in solvent
化学式

C20H17ClF4N4O4S
分子量 520.88 CAS No. 1146699-66-2
Solubility (25°C)* 体外 DMSO 104 mg/mL (199.66 mM)
Water Insoluble
Ethanol Insoluble
* <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 Avagacestat (BMS-708163) is a potent, selective, orally bioavailable γ-secretase inhibitor of Aβ40 and Aβ42 with IC50 of 0.3 nM and 0.27 nM, demonstrating a 193-fold selectivity against Notch. Phase 2.
in vitro BMS-708163 exhibits weaker selectivity for inhibition of Notch processing with 193-fold IC50 value. [1]
in vivo Oral administration of BMS-708163 significantly reduces Aβ40 levels for sustained periods in brain, plasma, and cerebrospinal fluid in rats and dogs. BMS-708163 has no dose-limiting effects in dogs (3 mg/kg during 6 months), with a high brain to plasma ratio (2.4). [1]
特徴 Appears to be more “notch sparing” than semagacestat (LY450139).

プロトコル(参考用のみ)

キナーゼアッセイ Inhibition of Aβ formation
BMS-708163 is assayed for Aβ40 or Aβ42 inhibition in cells using H4 APP751 SWE clone 8.20, an H4 neuroglioma cell line stably expressing the Swedish mutant of APP751. Cells are maintained in log phase through twice weekly passage at a 1:20 dilution. For IC50 determinations, 30 μL cells (1.5×104 cells/well) in DMEM media containing 0.0125% BSA are seeded directly into 384-well plates containing 0.1 μL serially diluted BMS-708163 in DMSO. Following incubation for 19 hours in 5% CO2 at 37 °C, plates are briefly centrifuged (103 rpm, 5 min). A 10 μL aliquot from each well is transferred to a second assay plate for Aβ40 measurements. Antibody cocktails are freshly prepared by dilution into 40 mM Tris-HCl (pH 7.4) with 0.2% BSA and added to assay plates. For Aβ42 measurements, antibodies specific for the Aβ42 neoepitope (565, developed at Bristol-Myers Squibb; conjugated to the Wallac reagent) and the N-terminal sequence of Aβ peptide (26D6, developed at SIBIA/Bristol-Myers Squibb; conjugated to APC) are mixed and 20 μL of the mixture is added to each well of the incubated cell plate yielding a final concentration of 0.8 ng/well 565 and 75 ng/well 26D6. For the Aβ40 measurements, antibodies specific for the Aβ40 neoepitope (TSD, developed at Bristol-Myers Squibb; conjugated to the Wallac reagent) and 26D6 as described above are mixed and 20 μL of the mixture is added to the 10 μL aliquots which have been removed previously from the cell plate yielding a final concentration of 1.6 ng/well TSD and 17.5 ng/well 26D6. Assay plates containing antibodies are sealed with aluminum foil and incubated overnight at 4 °C. Signal is determined using a Viewlux counter and IC50 values are determined.
動物実験 動物モデル Female Harlan Sprague-Dawley rats or ATM-405-142K9 with 7- 10 month old Na?ve, grade II beagles
投薬量 10 mg/kg (rats) or 2.5 mg/kg (dogs)
投与方法 Dosed daily by oral gavage

カスタマーフィードバック

Data from [Stem Cells, 2014, 32(1), 301-12]

Data from [Stem Cells, 2014, 32(1), 301-12]

Data from [Data independently produced by J Biol Chem, 2014, 289(30), 20871-8]

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：

Multi-omics characterization of autophagy-related molecular features for therapeutic targeting of autophagy [ Nat Commun, 2022, 13(1):6345] PubMed: 36289218
Establishment and characterization of immortalized sweat gland myoepithelial cells [ Sci Rep, 2022, 12(1):7] PubMed: 34997030
Structural basis of γ-secretase inhibition and modulation by small molecule drugs [ Cell, 2021, 184(2):521-533.e14] PubMed: 33373587
Carboxy-terminal fragment of amyloid precursor protein mediates lipid droplet accumulation upon γ-secretase inhibition [ Biochem Biophys Res Commun, 2021, 570:137-142] PubMed: 34280617
Activation of notch 3/c-MYC/CHOP axis regulates apoptosis and promotes sensitivity of lung cancer cells to mTOR inhibitor everolimus. [ Biochem Pharmacol, 2020, 175:113921] PubMed: 32201213
A novel human colon signet-ring cell carcinoma organoid line: establishment, characterization and application [ Carcinogenesis, 2020, 41(7):993-1004] PubMed: 31740922
RAC1P29S Induces a Mesenchymal Phenotypic Switch via Serum Response Factor to Promote Melanoma Development and Therapy Resistance [ Cancer Cell, 2019, 36(1):68-83] PubMed: 31257073
EGFL7 Antagonizes NOTCH Signaling and Represents a Novel Therapeutic Target in Acute Myeloid Leukemia. [ Clin Cancer Res, 2019, 10.1158/1078-0432.CCR-19-2479] PubMed: 31672772
Wild-type TP53 defined gamma-secretase inhibitor sensitivity and synergistic activity with doxorubicin in GSCs. [ Am J Cancer Res, 2019, 9(8):1734-1745] PubMed: 31497354
Iron dysregulates APP processing accompanying with sAPPα cellular retention and β-secretase inhibition in rat cortical neurons [Chen YT, et al. Acta Pharmacol Sin, 2018, 39(2):177-183] PubMed: 28836584

長期の保管のために-20°Cの下で製品を保ってください。

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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