Capivasertib (AZD5363)

製品コードS8019 バッチS801904

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

C21H25ClN6O2
分子量 428.92 CAS No. 1143532-39-1
Solubility (25°C)* 体外 DMSO 86 mg/mL (200.5 mM)
Ethanol 22 mg/mL (51.29 mM)
Water 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 Capivasertib (AZD5363) potently inhibits all isoforms of Akt(Akt1/Akt2/Akt3) with IC50 of 3 nM/8 nM/8 nM in cell-free assays, similar to P70S6K/PKA and lower activity towards ROCK1/2. Phase 2.
in vitro AZD5363 is a potent Akt inhibitor with IC50 of 3 nM, 8 nM and 8 nM for Akt1, Akt2 and Akt3, respectively. [1] AZD5363 inhibits phosphorylation of AKT substrates in cells with a potency of approximately 0.3 to 0.8 μM. AZD5363 inhibits the proliferation of 41 of 182 solid and hematologic tumor cell lines with a potency of < 3 μM. [2] Activating mutations in PIK3CA, loss or inactivation of tumor suppressor PTEN, or HER2 amplification all are significantly predictive of responsiveness to AZD5363. Additionally, correlation is also seen between the RAS mutation status of cell lines and resistance to AZD5363. [1]
in vivo Oral dosing of AZD5363 (100, 300 mg/kg) to nude mice causes dose- and time-dependent reduction of PRAS40, GSK3β, and S6 phosphorylation in BT474c xenografts, reversible increases in blood glucose concentrations, and dose-dependent decreases in 2[18F]fluoro-2-deoxy-d-glucose (18F-FDG) uptake in U87-MG xenografts. Chronic oral dosing of AZD5363 (130, 200, and 300 mg/kg) causes dose-dependent growth inhibition of xenografts derived from various tumor types, including HER2+ breast cancer models that are resistant to trastuzumab. AZD5363 also significantly enhances the antitumor activity of docetaxel, lapatinib, and trastuzumab in breast cancer xenografts. [2]
特徴 Moderate preclinical tolerability, and PD characteristics of an AKT inhibitor. Distinct profile from other AKT inhibitors in clinical development.

プロトコル(参考用のみ)

キナーゼアッセイ Caliper Off-Chip Incubation Mobility Shift assay
The ability of AZD5363 and other compounds to inhibit the activity of AKT1, AKT2, and AKT3 is evaluated by the Caliper Off-Chip Incubation Mobility Shift assay. Active recombinant AKT1, AKT2, or AKT3 are incubated with a 5-FAM-labeled custom-synthesized peptide substrate together with increasing concentrations of inhibitor. Final reactions contained 1 to 3 nM AKT1, AKT2, or AKT3 enzymes; 1.5 mM peptide substrate; ATP at K m for each AKT isoform; 10 mM MgCl2, 4 mM DTT, 100 mM HEPES, and 0.015% Brij-35. The reactions are incubated at room temperature for 1 hour and stopped by the addition of buffer containing 100 mM HEPES, 0.015% Brij-35 solution, 0.1% coating reagent, 40 mM EDTA, and 5% DMSO. Plates are then analyzed using a Caliper LC3000, allowing for separation of peptide substrate and phosphorylated product by electrophoresis with subsequent detection and quantification of laser induced fluorescence.
細胞アッセイ 細胞株 182 solid and hematologic tumor cell lines
濃度 ~30 μM
反応時間 72 hours
実験の流れ Cell proliferation assay is determined by 2 methods, MTS and Sytox Green. Briefly, cells are seeded in 96-well plates and incubated overnight at 37 ℃, 5% CO2. Cells are then exposed to concentrations of AZD5363 ranging from 30 to 0.003μM for 72 hours. For the MTS endpoint, cell proliferation is measured by the CellTiter AQueous Non-Radioactive Cell Proliferation Assay reagent in accordance with the manufacturer's protocol. For the Sytox Green endpoint, Sytox Green nucleic acid dye diluted in TBS-EDTA buffer is added to cells (final concentration of 0.13 μM) and the number of dead cells detected using an Acumen Explorer. Cells are then permeabilized by the addition of saponin (0.03% final concentration, diluted in TBS-EDTA buffer), incubated overnight and a total cell count measured. Predose measurements are made for both MTS and Sytox Green endpoints, and concentration needed to reduce the growth of treated cells to half that of untreated cells values are determined using absorbance readings (MTS) or live cell counts.
動物実験 動物モデル Female nude mice and male SCID mice with BT474c, U87MG, KPL-4, HCC-1187 xenografts.
投薬量 130 mg/Kg - 300 mg/Kg
投与方法 p.o.

カスタマーフィードバック

Data from [Data independently produced by Cell Commun Signal, 2014, 12(1), 61]

Data from [Data independently produced by PLoS One, 2014, 9(10), e108780]

Data from [Data independently produced by , , Clin Cancer Res, 2016, 22(4):1018-27]

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：

Dual targeting of the androgen receptor and PI3K/AKT/mTOR pathways in prostate cancer models improves antitumor efficacy and promotes cell apoptosis [ Mol Oncol, 2024, 10.1002/1878-0261.13577] PubMed: 38225213
Dual Targeting of Apoptotic and Signaling Pathways in T-Lineage Acute Lymphoblastic Leukemia [ Clin Cancer Res, 2023, 29(16):3151-3161] PubMed: 37363966
Mediation of PKM2-dependent glycolytic and non-glycolytic pathways by ENO2 in head and neck cancer development [ J Exp Clin Cancer Res, 2023, 42(1):1] PubMed: 36588153
Dual Targeting of Apoptotic and Signaling Pathways in T-Lineage Acute Lymphoblastic Leukemia [ Clin Cancer Res, 2023, 29(16):3151-3161] PubMed: 37363966
Crosstalk between tumor acidosis, p53 and extracellular matrix regulates pancreatic cancer aggressiveness [ Int J Cancer, 2023, 152(6):1210-1225] PubMed: 36408933
FAP is critical for ovarian cancer cell survival by sustaining NF-κB activation through recruitment of PRKDC in lipid rafts [ Cancer Gene Ther, 2023, 30(4):608-621] PubMed: 36494579
Suppression of androgen receptor signaling induces prostate cancer migration via activation of the CCL20-CCR6 axis [ Cancer Sci, 2023, 114(4):1479-1490] PubMed: 36479732
Suppression of androgen receptor signaling induces prostate cancer migration via activation of the CCL20-CCR6 axis [ Cancer Sci, 2023, 114(4):1479-1490] PubMed: 36479732
Bcl-xL Is a Key Mediator of Apoptosis Following KRASG12C Inhibition in KRASG12C-mutant Colorectal Cancer [ Mol Cancer Ther, 2023, 22(1):135-149] PubMed: 36279564
Bcl-xL Is a Key Mediator of Apoptosis Following KRASG12C Inhibition in KRASG12C-mutant Colorectal Cancer. [ Mol Cancer Ther, 2023, (1): 135–149.] PubMed: None

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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