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Purity: =99.27%
Capivasertib (formerly known as AZD5363; Truqap), a novel pyrrolopyrimidine-derived compound, is a potent, orally bioavailable pan-AKT kinase inhibitor with potential anticancer activity. It exhibits IC50 of 3, 7 and 7 nM for Akt1,Akt2 and Akt3, respectively. AKT is a key node in the most frequently deregulated signaling network in human cancer. AZD5363 inhibited all AKT isoforms with a potency of 10 nmol/L or less and inhibited phosphorylation of AKT substrates in cells with a potency of approximately 0.3 to 0.8 μmol/L. AZD5363 monotherapy inhibited the proliferation of 41 of 182 solid and hematologic tumor cell lines with a potency of 3 μmol/L or less. Cell lines derived from breast cancers showed the highest frequency of sensitivity. There was a significant relationship between the presence of PIK3CA and/or PTEN mutations and sensitivity to AZD5363 and between RAS mutations and resistance. Oral dosing of AZD5363 to nude mice caused dose- and time-dependent reduction of PRAS40, GSK3β, and S6 phosphorylation in BT474c xenografts (PRAS40 phosphorylation EC(50) ~ 0.1 μmol/L total plasma exposure), reversible increases in blood glucose concentrations, and dose-dependent decreases in 2[18F]fluoro-2-deoxy-D-glucose ((18)F-FDG) uptake in U87-MG xenografts. Chronic oral dosing of AZD5363 caused dose-dependent growth inhibition of xenografts derived from various tumor types, including HER2(+) breast cancer models that are resistant to trastuzumab. AZD5363 also significantly enhanced the antitumor activity of docetaxel, lapatinib, and trastuzumab in breast cancer xenografts. It is concluded that AZD5363 is a potent inhibitor of AKT with pharmacodynamic activity in vivo, has potential to treat a range of solid and hematologic tumors as monotherapy or a combinatorial agent, and has potential for personalized medicine based on the genetic status of PIK3CA, PTEN, and RAS. AZD5363 is currently in phase I clinical trials. Additionally, AZD5363 significantly increased the antitumor effects of trastuzumab, lapatinib, and docetaxel in breast cancer xenografts. Conclusion: Based on the genetic status of PIK3CA, PTEN, and RAS, AZD5363 is a potent AKT inhibitor with pharmacodynamic activity in vivo and the potential to treat a variety of solid and hematologic tumors as a single agent or in combination. It also has the potential to be used in personalized medicine. Phase I clinical trials for AZD5363 are currently underway. Capivasertib (Truqap) was approved in 2023 by FDA for treating Breast cancer.
| Targets |
Akt1 (IC50 = 3 nM); Akt2 (IC50 = 7 nM); Akt3 (IC50 = 7 nM); ROCK2 (IC50 = 60 nM); ROCK1 (IC50 = 470 nM); PKA (IC50 = 7 nM); P70S6K (IC50 = 6 nM); Autophagy
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| ln Vitro |
AZD5363 is a potent Akt inhibitor with IC50 of 3 nM, 8 nM and 8 nM for Akt1, Akt2 and Akt3, respectively.[1] With a potency of roughly 0.3 to 0.8 μM, AZD5363 prevents the phosphorylation of AKT substrates in cells. With a potency of less than < 3 μM, AZD5363 prevents the growth of 41 of 182 solid and hematologic tumor cell lines.[2] Significantly predicting factors for responsiveness to AZD5363 include activating mutations in PIK3CA, loss or inactivation of the tumor suppressor PTEN, and HER2 amplification. Furthermore, a connection is seen between a cell line's RAS mutation status and its resistance to AZD5363.[1]
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| ln Vivo |
Oral administration of AZD5363 (100, 300 mg/kg) to naked mice results in reversible increases in blood glucose levels, dose-dependent decreases in 2[18F]fluoro-2-deoxy-d-glucose (18F-FDG) uptake in U87-MG xenografts, and dose-dependent reductions in PRAS40, GSK3, and S6 phosphorylation in BT474c xenografts. Chronic oral administration of AZD5363 (130, 200, and 300 mg/kg) results in dose-dependent growth inhibition of xenografts derived from various tumor types, including trastuzumab-resistant HER2+ breast cancer models. Additionally, in breast cancer xenografts, AZD5363 significantly increases the antitumor activity of docetaxel, lapatinib, and trastuzumab.[2]
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| Enzyme 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. The final reactions contained 1 to 3 nM AKT1, AKT2, or AKT3 enzymes, 1.5 mM peptide substrate, ATP at Km for each AKT isoform, 10 mM MgCl2, 4 mM DTT, 100 mM HEPES, and 0.015% Brij-35. The reactions are allowed to proceed for an hour at room temperature before being stopped with the addition of a buffer containing 40 mM EDTA, 5% DMSO, 0.1% coating reagent, 0.1% Brij-35 solution, and 100 mM HEPES. After that, plates are examined on a Caliper LC3000, allowing for the electrophoretic separation of the peptide substrate and phosphorylated product and the subsequent detection and quantification of laser-induced fluorescence.
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| Cell Assay |
MTS and Sytox Green are the two methods used to measure cell proliferation. Briefly, cells are plated in 96-well dishes and incubated at 37 °C with 5% CO2 for an entire night. Following that, cells are subjected to AZD5363 concentrations ranging from 30 to 0.003 μM for 72 hours. Cell proliferation is assessed for the MTS endpoint using the CellTiter AQueous Non-Radioactive Cell Proliferation Assay reagent in accordance with the manufacturer's instructions. The Sytox Green endpoint, Sytox Green nucleic acid dye to cells at a final concentration of 0.13 μM and counting the number of dead cells using an Acumen Explorer. Following saponin permeabilization (0.03% final concentration, diluted in TBS-EDTA buffer), cells are incubated for an overnight period to determine the total cell count. Predose measurements are taken for Sytox Green and MTS endpoints, and the concentration needed to cut treated cell growth in half compared to untreated cell growth is calculated using live cell counts or MTS absorbance readings.
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| Animal Protocol |
Mice: Specific, pathogen-free, female nude mice (nu/nu: Alpk) and male SCID mice (SCID/CB17; 786-0 xenograft studies) are used. The mice are randomly assigned to control and treatment groups once the mean tumor sizes reach about 0.2 cm3. The treatment groups received RP-56976, which was dissolved in 2.6% ethanol in injectable water, once on day 1, at 15 or 5 mg/kg once a week, and Capivasertib (AZD5363), which was dissolved in a 10% DMSO 25% w/v Kleptose HPB (Roquette) buffer by oral gavage. When used in conjunction with Capivasertib (AZD5363), RP-56976 is given an hour before the oral dose. The control group received the DMSO/Kleptose buffer alone, twice daily by oral gavage. For the duration of the study, tumor volumes (as determined by caliper), animal weight, and tumor condition are noted twice a week. By using CO2 euthanasia, mice are sacrificed. Using the formula: (length×width)×√(length×width)×(π/6), the tumor volume is calculated by considering length to be the longest diameter across the tumor and width to be the corresponding perpendicular diameter. By comparing the variations in tumor volume between the control and treated groups, growth inhibition from the onset of treatment is evaluated.
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| References |
| Molecular Formula |
C21H25CLN6O2
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|---|---|
| Molecular Weight |
428.9152
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| Exact Mass |
428.17275
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| Elemental Analysis |
C, 58.81; H, 5.87; Cl, 8.27; N, 19.59; O, 7.46
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| CAS # |
1143532-39-1
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| Related CAS # |
(R)-Capivasertib;1143532-51-7
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| Appearance |
white solid powder
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| SMILES |
C1CN(CCC1(C(=O)N[C@@H](CCO)C2=CC=C(C=C2)Cl)N)C3=NC=NC4=C3C=CN4
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| InChi Key |
JDUBGYFRJFOXQC-KRWDZBQOSA-N
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| InChi Code |
InChI=1S/C21H25ClN6O2/c22-15-3-1-14(2-4-15)17(6-12-29)27-20(30)21(23)7-10-28(11-8-21)19-16-5-9-24-18(16)25-13-26-19/h1-5,9,13,17,29H,6-8,10-12,23H2,(H,27,30)(H,24,25,26)/t17-/m0/s1
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| Chemical Name |
4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide
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| Synonyms |
Capivasertib; AZD-5363; AZD5363; AZD 5363; Truqap
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: 86~125 mg/mL (200.5~291.4 mM)
Ethanol: ~2 mg/mL (~4.0 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.85 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.85 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.85 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3314 mL | 11.6572 mL | 23.3144 mL | |
| 5 mM | 0.4663 mL | 2.3314 mL | 4.6629 mL | |
| 10 mM | 0.2331 mL | 1.1657 mL | 2.3314 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Status | Interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT05348577 | Recruiting | Drug: capivasertib Drug: docetaxel |
Prostate Cancer | AstraZeneca | March 25, 2022 | Phase 3 |
| NCT04493853 | Recruiting | Drug: Capivasertib Other: Placebo |
Hormone-Sensitive Prostate Cancer |
AstraZeneca | July 13, 2020 | Phase 3 |
| NCT05593497 | Not yet recruiting | Drug: Capivasertib Drug: abiraterone acetate |
High-Risk Prostate Cancer | VA Office of Research and Development |
October 16, 2023 | Phase 2 |
| NCT05720260 | Recruiting | Drug: Goserelin Drug: Fulvestrant |
Metastatic Breast Cancer ER Positive Breast Cancer |
National Taiwan University Hospital |
January 17, 2023 | Phase 2 |
| NCT04862663 | Recruiting | Drug: Capivasertib Drug: Fulvestrant |
Locally Advanced (Inoperable) | AstraZeneca | May 10, 2021 | Phase 3 |
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AZD5363 inhibits proliferation of a subset of cancer cell linesin vitro. A, panels of cell lines derived from different tumor types were screened in a standard MTS cell proliferation assay.B, relationship of sensitive (GI50< 3μmol/L) and highly sensitive (GI50< 1 μmol/L) cell lines with genetic status.Mol Cancer Ther. 2012 Apr;11(4):873-87. |
Continuous monotherapy dosing of AZD5363 inhibits growth of xenografts. Xenografts growing in immunodeficient mice were dosed as indicated throughout the experimental period (A–C) or for 16 days before dosing was stopped and recovery of tumor growth monitored (D).Mol Cancer Ther. 2012 Apr;11(4):873-87. |
AZD5363 has pharmacodynamic activity in BT474c xenografts and increases blood glucose concentrations in nonfasting nude mice.Mol Cancer Ther. 2012 Apr;11(4):873-87. |
8F-FDG-PET imaging shows that AZD5363 reduces18F-FDG uptake in U87-MG xenografts: relationship with tumor pharmacodynamics and growth inhibitionin vivo.Mol Cancer Ther. 2012 Apr;11(4):873-87. |
AZD5363 enhances efficacy of trastuzumab, lapatinib, and docetaxel in breast cancer xenograft models.Mol Cancer Ther. 2012 Apr;11(4):873-87. |
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