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| 25mg |
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Purity: ≥98%
AZD8835 is a novel, selective, and orally bioavailable inhibitor of the class I (PI3K) catalytic subunit alpha (PIK3CA) PI3Kα and PI3Kδ with IC50s of 6.2 and 5.7 nM, respectively with potential antineoplastic activity. In the PI3K/Akt (protein kinase B)/mammalian target of rapamycin (mTOR) pathway, the PI3K alpha inhibitor AZD8835 specifically binds to and inhibits PIK3CA and its mutant forms. This causes apoptosis in PIK3CA-expressing tumor cells as well as growth inhibition. This medication may be more effective and less harmful than pan-PI3K inhibitors because it targets PIK3CA specifically. The PI3K/Akt/mTOR pathway is frequently dysregulated in solid tumors, which promotes tumor cell growth, survival, and resistance to chemotherapy and radiotherapy.
| Targets |
PI3Kδ (IC50 = 5.7 nM); PI3Kα (IC50 = 6.2 nM); PI3Kα-H1047R (IC50 = 5.8 nM); PI3Kα-E545K (IC50 = 6 nM); PI3Kγ (IC50 = 90 nM); PI3Kβ (IC50 = 431 nM)
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| ln Vitro |
AZD8835 is a potent inhibitor of PI3Kα (wild type, E545K and H1047R mutations) and PI3Kδ with excellent selectivity vs. PI3Kβ, PI3Kγ and an excellent general kinase selectivity. AZD8835 is a potent inhibitor of p-Akt in cells sensitive to PI3Kα inhibition (IC50=0.057 μM in PIK3CA mutant human breast ductal carcinoma BT474 cell line) and in cells sensitive to PI3Kδ inhibition (IC50=0.049 μM in JeKo-1 B cell line), but not to cells sensitive to PI3Kβ inhibition (IC50=3.5 μM in PTEN null breast adenocarcinoma MDA-MB-468 cell line) or PI3Kγ inhibition (IC50=0.53 μM in monocytic RAW264 cell line)[2].
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| ln Vivo |
AZD8835 exhibits high metabolic stability and suitable physical properties for oral administration, and it has antitumor efficacy in corresponding breast cancer xenograft models when dosed continuously[1][2].
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| Enzyme Assay |
The selectivity profile of AZD8835 (Compound 25) among the class I PI3K isoforms is tested in enzyme and cell based assays. At the enzyme level, AZD8835 is a potent mixed inhibitor of PI3Kα (IC506.2 nM) and PI3Kδ (IC505.7 nM), with selectivity against PI3Kβ (IC50431 nM) and PI3Kγ (IC5090 nM). AZD8835 is also a potent inhibitor of the commonly occurring PI3Kα mutants, PI3Kα- E545K (IC506 nM) and PI3Kα-H1047R (IC505.8 nM). In cell-based assays assessing the ability to inhibit Akt phosphorylation, AZD8835 is a potent inhibitor in cells sensitive to PI3Kα inhibition (IC5057 nM inPIK3CAmutant human breast ductal carcinoma BT474 cell line) and in cells sensitive to PI3Kδ inhibition (IC5049 nM in Jeko-1 B cell line, but not to cells sensitive to PI3Kβ inhibition (IC503.5 μM in PTEN null breast adenocarcinoma MDA-MB-468 cells) or to PI3Kγ inhibition (IC50530 nM in monocytic RAW264 cell line).
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| Cell Assay |
BT474, MCF7, or T47D cells are seeded in 384-well plates at a density of 500–2,000 cells per well and incubated overnight. Over the course of several days, cells are dosed with a compound or compounds, and cell confluency is measured every four hours.
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| Animal Protocol |
CD1 mice
0.1 mL/10 g mouse oral administration |
| References | |
| Additional Infomation |
PI3Kalpha Inhibitor AZD8835 is an orally bioavailable inhibitor of the class I phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) catalytic subunit alpha (PIK3CA), with potential antineoplastic activity. PI3K alpha inhibitor AZD8835 selectively binds to and inhibits PIK3CA and its mutated forms, in the PI3K/Akt (protein kinase B) /mammalian target of rapamycin (mTOR) pathway. This results in both apoptosis and growth inhibition in PIK3CA-expressing tumor cells. By specifically targeting PIK3CA, this agent may be more efficacious and less toxic than pan-PI3K inhibitors. Dysregulation of the PI3K/Akt/mTOR pathway is often found in solid tumors and results in the promotion of tumor cell growth, survival, and resistance to chemo- and radio-therapy. PIK3CA, one of the most frequently mutated oncogenes, encodes the p110-alpha catalytic subunit of the class I PI3K.
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| Molecular Formula |
C22H31N9O3
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|---|---|
| Molecular Weight |
469.54
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| Exact Mass |
469.254
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| Elemental Analysis |
C, 56.28; H, 6.65; N, 26.85; O, 10.22
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| CAS # |
1620576-64-8
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| Related CAS # |
1620576-64-8
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| PubChem CID |
76685059
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.5±0.1 g/cm3
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| Boiling Point |
784.0±70.0 °C at 760 mmHg
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| Flash Point |
427.9±35.7 °C
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| Vapour Pressure |
0.0±2.9 mmHg at 25°C
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| Index of Refraction |
1.703
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| LogP |
3.33
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
34
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| Complexity |
685
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC(C1OC(C2=C(N)N=CC(C3N(N=C(N=3)C3CCN(C(=O)CCO)CC3)CC)=N2)=NN=1)(C)C
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| InChi Key |
ZGRDYKFVDCFJCZ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H31N9O3/c1-5-31-19(26-18(29-31)13-6-9-30(10-7-13)15(33)8-11-32)14-12-24-17(23)16(25-14)20-27-28-21(34-20)22(2,3)4/h12-13,32H,5-11H2,1-4H3,(H2,23,24)
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| Chemical Name |
1-(4-(5-(5-amino-6-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-hydroxypropan-1-one
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| Synonyms |
AZD-8835; AZD 8835; AZD8835
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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: ~93 mg/mL (~198.1 mM)
Water: <1 mg/mL Ethanol: <1 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 0.83 mg/mL (1.77 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 8.3 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of 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: ≥ 0.83 mg/mL (1.77 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 8.3 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: ≥ 0.83 mg/mL (1.77 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 | 2.1297 mL | 10.6487 mL | 21.2974 mL | |
| 5 mM | 0.4259 mL | 2.1297 mL | 4.2595 mL | |
| 10 mM | 0.2130 mL | 1.0649 mL | 2.1297 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 |
| NCT02260661 | Completed | Drug: AZD8835 | Advanced Solid Malignancies |
AstraZeneca | November 2014 | Phase 1 |
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