Antibodies
AZD5363
- 貨號 Cat. No.
- S8019
- 規格 Size
- 5~200mg
- 品牌 Brand
- Selleckchem
Description
AZD5363
Catalog No.S8019
AZD5363 potently inhibits all isoforms of Akt(Akt1/Akt2/Akt3) with IC50 of 3 nM/8 nM/8 nM, similar to P70S6K/PKA and lower activity towards ROCK1/2. Phase 1/2.
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Biological Activity
| Description | AZD5363 potently inhibits all isoforms of Akt(Akt1/Akt2/Akt3) with IC50 of 3 nM/8 nM/8 nM, similar to P70S6K/PKA and lower activity towards ROCK1/2. Phase 1/2. | |||||
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| Targets | Akt1 | Akt2 | Akt3 | |||
| IC50 | 3 nM | 8 nM | 8 nM [1] | |||
| 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] | |||||
| Features | Moderate preclinical tolerability, and PD characteristics of an AKT inhibitor. Distinct profile from other AKT inhibitors in clinical development. | |||||
Protocol(Only for Reference)
Kinase Assay: [1]
| 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. |
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Cell Assay: [2]
| Cell lines | 182 solid and hematologic tumor cell lines |
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| Concentrations | ~30 μM |
| Incubation Time | 72 hours |
| Method | 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 manufacturers 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. |
Animal Study: [2]
| Animal Models | Female nude mice and male SCID mice with BT474c, U87MG, KPL-4, HCC-1187 xenografts. |
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| Dosages | 130 mg/Kg - 300 mg/Kg |
| Administration | p.o. |
References
Clinical Trial Information( data from http://clinicaltrials.gov)
| NCT Number | Recruitment | Conditions | Sponsor /Collaborators | Start Date | Phases |
|---|---|---|---|---|---|
| NCT01226316 | Recruiting | Advanced Solid Malignancy|Safety and Tolerability|Pharmacokinetics|Pharmacodynamics|Tumour Response|Advanced or Metastatic Breast Cancer|Ovarian Cancer|Cervical Cancer|Endometrial Cancer|PIK3CA|AKT1|ER+|HER2+ | AstraZeneca | 2010-11 | Phase 1 |
| NCT01353781 | Recruiting | Advanced Solid Malignancy|Advanced Solid Tumor | AstraZeneca | 2011-06 | Phase 1 |
| NCT01625286 | Recruiting | Advanced or Metastatic Breast Cancer,|ER+ve Advanced or Metastatic Breast Cancer. | AstraZeneca | 2012-10 | Phase 1|Phase 2 |
| NCT01692262 | Recruiting | Metastatic Castrate-Resistant Prostate Cancer (mCRPC),|Efficacy,|Safety and Tolerability,|Pharmacokinetics,|Pharmacodynamics,|Tumour Response. | AstraZeneca | 2012-10 | Phase 1 |
Chemical Information
Download AZD5363 SDFDownload AZD5363 SDFDownload AZD5363 SDF
| Molecular Weight (MW) | 428.92 |
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| Formula | C21H25ClN6O2 |
| CAS No. | 1143532-39-1 |
| Storage | 3 years -20℃Powder |
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| 6 months-80℃in DMSO | |
| Syonnyms | N/A |
| Solubility (25°C) * | In vitro | DMSO | 86 mg/mL (200 mM) |
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| Water | <1 mg/mL (<1 mM) | ||
| Ethanol | <1 mg/mL (<1 mM) | ||
| * <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. | |||
| Chemical Name | 4-Piperidinecarboxamide, 4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- |
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Preparing Stock Solutions
| Stock Solution (1ml DMSO) | 1mM | 10mM | 20mM | 30mM |
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| Mass(mg) | 0.42892 | 4.2892 | 8.5784 | 12.8676 |
