AZD5363

AKT inhibitor,pyrrolopyrimidine derived CAS# 1143532-39-1

AZD5363

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Chemical structure

AZD5363

3D structure

Chemical Properties of AZD5363

Cas No. 1143532-39-1 SDF Download SDF
PubChem ID 25227436 Appearance Powder
Formula C21H25ClN6O2 M.Wt 428.92
Type of Compound N/A Storage Desiccate at -20°C
Synonyms AZD-5363; AZD 5363; Cc-638
Solubility DMSO : ≥ 21.5 mg/mL (50.13 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name 4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide
SMILES C1CN(CCC1(C(=O)NC(CCO)C2=CC=C(C=C2)Cl)N)C3=NC=NC4=C3C=CN4
Standard InChIKey JDUBGYFRJFOXQC-KRWDZBQOSA-N
Standard InChI 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
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of AZD5363

DescriptionAZD5363 is a pyrrolopyrimidine-derived inhibitor of all Akt isoforms with IC50 values of <10 nM.
TargetsAkt    
IC50<10 nM     

Protocol

Cell experiment: [1]

Cell lines

GSK3 in BT474c (Her2þ PIK3CAmutant breast), LNCaP (PTEN-null prostate) and MDA-MB-468 (PTEN-null breast) cancer cells

Preparation method

The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months.

Reacting condition

pGSK3β (IC50: 0.76 μM in BT474c, 0.06 μM in LNCaP, 0.38 μM in MDA-MB-468) pPRAS40 (IC50: 0.31 μM in BT474c, 0.22 μM in LNCaP, 0.39 μM in MDA-MB-468) pFOXO3a translocation (IC50: 0.69 μM in BT474c)

Applications

AZD5363 inhibited phosphorylation of AKT substrates with IC50 values of 0.06 to 0.76 μM in the 3 cell lines. AZD5363 also effectively inhibited phosphorylation of S6 and 4E-BP1 in BT474c cells and LNCaP cells.

Animal experiment : [1]

Animal models

Nude mice bearing BT474c xenografts

Dosage form

The treatment groups received 300 or 100 mg/kg acute dose of AZD5363 solubilized in a DMSO/Kleptose buffer, by oral gavage.

Application

Oral dosing of AZD5363 to nude mice caused dose and time-dependent reduction of PRAS40, GSK3, and S6 phosphorylation. Following a 300 mg/kg dose of AZD 5363, phosphorylation of all 3 biomarkers was significantly inhibited for at least 24 hours. 100 mg/kg dose of AZD5363 significantly inhibited phosphorylation of the 3 biomarkers was for at least 8 hours.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

[1] Davies B R, Greenwood H, Dudley P, et al. Preclinical pharmacology of AZD5363, an inhibitor of AKT: pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic background. Molecular cancer therapeutics, 2012, 11(4): 873-887.

AZD5363 Dilution Calculator

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Preparing Stock Solutions of AZD5363

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.3314 mL 11.6572 mL 23.3144 mL 46.6287 mL 58.2859 mL
5 mM 0.4663 mL 2.3314 mL 4.6629 mL 9.3257 mL 11.6572 mL
10 mM 0.2331 mL 1.1657 mL 2.3314 mL 4.6629 mL 5.8286 mL
50 mM 0.0466 mL 0.2331 mL 0.4663 mL 0.9326 mL 1.1657 mL
100 mM 0.0233 mL 0.1166 mL 0.2331 mL 0.4663 mL 0.5829 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on AZD5363

AZD5363 is a novel, potent phosphoinositide 3-kinase (PI3K)/Akt pathway inhibitor with IC50 value of ~200nM. [1]

AZD5363 is proved to inhibit castrate resistant prostate cancer (CRPC) progression. Clusterin (CLU) and autophagy will be induced which may work as cytoprotective responses which can affect the downstream PI3K/Akt signaling. [2] AZD5363 inhibits the growth of a lot of human tumor cells in a dose dependent manner. The mode of action could be monotherapy as well as in combination with HER2 inhibitors in breast cancer models. [3] It is suggested to induce cell apoptosis by measuring the expression of PARP cleavage, the activity of Caspase 3, et al. [1]

Most importantly, AZD5363 can target the PI3K/Akt-pathway in vivo significantly, thus reducing the serum PSA-levels and tumor volume, finally, it could postpone the progression to CRPC.[1]

References:
[1] Thomas C, Crafter C, Davies B, Zoubeidi A, Gleave ME. AZD5363, A novel AKT inhibitor, delays prostate cancer progression. The Journal of Urology. May 2011. 185(4S): e292-293.
[2] Kumano M, Zhang F, Shiota M, Crafter C, Davies B, Zoubeidi A, Gleave M. Clusterin knockdown enhances antitumor activity of a novel Akt inhibitor, AZD5363, through inhibition of autophagy in prostate cancer. The Journal of Urology. May 21 2012. e392.
[3] Davies BR, Greenwood H, Dudley P, et al. Preclinical Pharmacology of AZD5363, an Inhibitor of AKT: Pharmacodynamics, Antitumor Activity, and Correlation of Monotherapy Activity with Genetic Background. Mol. Cancer Ther. Arp 2012. 11: 873.

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References on AZD5363

Co-treatment of LY294002 or MK-2206 with AZD5363 Attenuates AZD5363-induced Increase in the Level of Phosphorylated AKT.[Pubmed:27793908]

Anticancer Res. 2016 Nov;36(11):5849-5858.

Clinical trials are in progress on AZD5363, an inhibitor of protein kinase B (AKT), to assess its effects on the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway. Cells treated with AKT inhibitors have been reported to activate alternative pathways in order to escape growth inhibition. AZD5363-sensitized Hs578T breast cancer cells displayed reduced levels of phosphorylated glycogen synthase kinase 3 beta (pGSK3beta). Interestingly, in AZD5363-treated cells, the level of phosphorylated (activated) AKT (pAKT) increased. Since pAKT positively correlates with cancer growth and survival, we aimed to identify conditions that could reduce AZD5363-induction of pAKT. We examined whether AZD5363 induction of pAKT could be reduced by co-treatment with inhibitors of the PI3K/AKT/mTOR pathway (LY294002, MK-2206, wortmannin, perifosine, rapamycin, everolimus, and temsirolimus). We observed that co-treatment of LY294002 or MK-2206 with AZD5363 reduced the level of pAKT. Since MK-2206 is clinically used, we propose that co-treatment using MK-2206 with AZD5363 would prove beneficial in blocking the AZD5363-induced pAKT signaling pathway. Our findings contribute to the development of AZD5363-based sensitization therapies for patients with cancer.

Safety and tolerability of AZD5363 in Japanese patients with advanced solid tumors.[Pubmed:26931343]

Cancer Chemother Pharmacol. 2016 Apr;77(4):787-95.

PURPOSE: Investigate the safety and tolerability of AZD5363 and define a recommended dose for evaluation in Japanese patients with advanced solid malignancies. METHODS: AZD5363 was administered orally as a single dose, and then the dose was escalated to twice daily (bid) in separate continuous (every day) and intermittent (4 days on, 3 days off [4/3] or 2 days on, 5 days off [2/5]) dosing schedules to reach recommended doses defined by dose-limiting toxicity (DLT). Doses for continuous, 4/3, and 2/5 intermittent dosing schedules were 80-400, 360-480, and 640 mg, respectively, and were informed by results from an equivalent study in Caucasian patients. RESULTS: Forty-one patients received AZD5363. DLTs were only experienced with continuous dosing. 97.6 % of patients reported at least one adverse event (AE); most common were diarrhea (78.0 %), hyperglycemia (68.3 %), nausea (56.1 %), and maculopapular rash (56.1 %). Grade >/=3 AEs were reported by 63.4 % of patients. Exposure of AZD5363 was generally dose proportional for both single and multiple doses. Single-dose pharmacokinetics of AZD5363 was generally predictive of multiple-dose pharmacokinetics. Confirmed partial responses were reported by two patients, both of whom were Akt1 (E17K) mutation positive. One patient in the 480 mg bid 4/3 dosing cohort maintained partial response for >2 years. CONCLUSIONS: Intermittent dosing of AZD5363 was more tolerable than continuous dosing. 480 mg bid intermittent 4/3 dosing for AZD5363 monotherapy was selected for further investigation. Preliminary evidence of antitumor activity was observed. Akt1 (E17K) is a potent driver mutation that may predict clinical response to AZD5363.

A novel AKT inhibitor, AZD5363, inhibits phosphorylation of AKT downstream molecules, and activates phosphorylation of mTOR and SMG-1 dependent on the liver cancer cell type.[Pubmed:26998062]

Oncol Lett. 2016 Mar;11(3):1685-1692.

Due to frequent phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway dysregulation, AKT is typically accepted as a promising anticancer therapeutic target. mTOR, in particular, represents a suitable therapeutic target for hepatocellular carcinoma, whilst suppressor with morphogenetic effect on genitalia family member-1 (SMG-1) is believed to serve a potential tumor suppressor role in human cancer. Despite SMG-1 and mTOR belonging to the same PI3K-related kinase family, the interactions between them are not yet fully understood. In the present study, a novel pyrrolopyrimidine-derived compound, AZD5363, was observed to suppress proliferation in liver cancer Hep-G2 and Huh-7 cells by inhibiting the phosphorylation of downstream molecules in the AKT signal pathway, in a dose- and time-dependent manner. AZD5363 activated the phosphorylation of mTOR, dependent on the liver cancer cell type, as it may have differing effects in various liver cancer cell lines. Additionally, AZD5363 also activated SMG-1 within the same liver cancer cells types, which subsequently activated the phosphorylation of mTOR. In conclusion, the present study indicates that AZD5363 inhibited phosphorylation of AKT downstream molecules, and activated phosphorylation of mTOR and SMG-1, dependent on the liver cancer type.

ProCAID: a phase I clinical trial to combine the AKT inhibitor AZD5363 with docetaxel and prednisolone chemotherapy for metastatic castration resistant prostate cancer.[Pubmed:28144789]

Invest New Drugs. 2017 Oct;35(5):599-607.

Background Docetaxel and prednisolone chemotherapy (DP) extends survival in metastatic castration resistant prostate cancer (mCRPC). However, emergent clinical resistance is almost inevitable. AKT pathway activation is highly prevalent in mCRPC contributing to disease progression and DP resistance. AZD5363 is a potent oral pan-AKT inhibitor with pre-clinical data indicating activity in mCRPC and synergy with docetaxel. Methods This phase I trial was to determine an AZD5363 recommended phase II dose (RP2D) for combination with DP. Eligibility criteria included chemotherapy naive mCRPC, PSA or radiographic disease progression and ECOG performance status 0 or 1. Treatment comprised DP (75 mg/m(2), IV, day 1 and 5 mg BID, PO, day 1-21 respectively for ten cycles) and AZD5363 to disease progression for all patients. We utilised a 3 + 3 dose escalation design to determine a maximum tolerated dose according to defined dose limiting toxicity criteria assessed using CTCAE version 4.03. Planned AZD5363 dose levels were 320 mg (DL1), 400 mg (DL2) and 480 mg (DL3), BID, PO, 4 days on/3 days off, from day 2 of each cycle. Results 10 patients were treated. Dose limiting toxicities affected 2 patients (grade 3 rash >/=5 days; grade 3 diarrhoea) in DL2. The commonest grade 3 or 4, AZD5363 related, symptomatic adverse events were rash and diarrhoea. Hyperglycaemia affected all patients but was self-limiting. PSA reduction to <50% at 12 weeks occurred in 7 patients. Conclusions The RP2D for AZD5363 is 320 mg BID, 4 days on/3 days off, in combination with full dose DP for mCRPC.

Description

Capivasertib (AZD5363) is a potent pan-AKT kinase inhibitor with IC50 of 3, 7 and 7 nM for Akt1,Akt2 and Akt3, respectively.

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