| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
|
||
| 10mg |
|
||
| 25mg |
|
||
| 50mg |
|
||
| 100mg |
|
||
| 250mg | |||
| 500mg | |||
| Other Sizes |
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)
AZD8835 targets PI3Kα (IC50 = 0.02 μM), PI3Kδ (IC50 = 0.03 μM) [1] AZD8835 shows moderate activity against PI3Kβ (IC50 = 0.3 μM) and weak activity against PI3Kγ (IC50 = 2.5 μM) [2] |
|---|---|
| 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].
In human cancer cell lines with PI3K pathway activation (MCF-7, BT474, HCT116, U87MG), AZD8835 (0.01–10 μM) inhibits cell proliferation in a dose-dependent manner, with IC50 values ranging from 0.08 to 0.9 μM. MCF-7 (breast cancer) and HCT116 (colon cancer) cells show highest sensitivity (IC50 = 0.08–0.12 μM) [1] - It blocks PI3K-AKT signaling: reduces phosphorylation of AKT (Ser473), GSK3β (Ser9), and S6 ribosomal protein (Ser235/236) in MCF-7 cells (Western blot), with maximal inhibition at 0.5 μM [1] - In BT474 cells, AZD8835 (0.1–1 μM) induces G1 cell cycle arrest (62% of cells in G1 vs. 45% control) and apoptosis (Annexin V-FITC/PI staining shows apoptotic rate ~42% at 0.5 μM) [1] - It exhibits high selectivity for class I PI3Ks: no significant inhibition of 40 unrelated kinases (e.g., mTOR, ERK1/2, JAK2, CDK2) at 10 μM (kinase selectivity panel assay) [2] - In human peripheral blood mononuclear cells (PBMCs), AZD8835 (0.05–1 μM) inhibits LPS-induced TNF-α and IL-6 production (IC50 = 0.1 μM and 0.15 μM, respectively) without affecting cell viability [2] |
| 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].
In a subcutaneous xenograft model of breast cancer (MCF-7 cells in nude mice), oral administration of AZD8835 (10 mg/kg/day) for 21 days inhibits tumor growth by ~70% compared to vehicle control. Tumor tissues show reduced p-AKT, p-S6, and Ki-67 expression (immunohistochemistry), and increased cleaved caspase-3 levels (Western blot) [1] - In a colon cancer xenograft model (HCT116 cells in nude mice), oral AZD8835 (15 mg/kg/day) for 28 days prolongs median survival from 32 days (control) to 56 days. It also reduces tumor angiogenesis (CD31 staining shows ~55% reduction in microvessel density) [1] - In a rat model of acute inflammation (carrageenan-induced paw edema), oral AZD8835 (5 mg/kg) reduces paw swelling by ~45% at 4 hours post-administration, with serum TNF-α and IL-6 levels reduced by ~50% [2] |
| 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).
Class I PI3K kinase activity assay: Recombinant human PI3Kα (p110α/p85α), PI3Kβ (p110β/p85α), PI3Kγ (p110γ/p101), and PI3Kδ (p110δ/p85α) were each incubated with phosphatidylinositol substrate, ATP, and reaction buffer (20 mM Tris-HCl pH 7.5, 10 mM MgCl2, 1 mM DTT) at 30°C for 60 minutes. AZD8835 was added at concentrations ranging from 0.001–10 μM. Phosphorylated PI (PIP3) was detected via HTRF assay (excitation 340 nm, emission 665 nm) using PIP3-specific antibodies. IC50 values were calculated by nonlinear regression of dose-response curves [1,2] - Kinase selectivity assay: AZD8835 (10 μM) was incubated with 40 purified kinases (including mTOR, ERK1/2, JAK2, CDK2, EGFR) and respective substrates/ATP under standard kinase assay conditions. Kinase activity was measured via radiometric or fluorescence-based assays, and inhibition percentage was calculated to confirm selectivity for class I PI3Ks [2] |
| 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.
Cancer cell proliferation and signaling assay: MCF-7/BT474/HCT116 cells (5×10³ per well) were seeded in 96-well plates, treated with AZD8835 (0.01–10 μM) for 48 hours. Cell viability was measured by CCK-8 assay to determine IC50. For signaling analysis, cells were treated with the drug (0.05–1 μM) for 24 hours, lysed, and Western blot was performed to detect p-AKT, AKT, p-GSK3β, GSK3β, p-S6, S6, and GAPDH [1] - Cell cycle and apoptosis assay: BT474 cells (1×10⁵ per well) were seeded in 6-well plates, treated with AZD8835 (0.1–1 μM) for 24 hours. Cell cycle was analyzed by PI staining and flow cytometry; apoptosis was detected by Annexin V-FITC/PI staining and flow cytometry [1] - PBMC cytokine production assay: Human PBMCs were isolated, seeded in 24-well plates, pretreated with AZD8835 (0.05–1 μM) for 1 hour, then stimulated with LPS (1 μg/mL) for 24 hours. Supernatants were collected, and TNF-α/IL-6 levels were quantified by ELISA [2] |
| Animal Protocol |
CD1 mice
0.1 mL/10 g mouse oral administration Breast cancer subcutaneous xenograft model: Nude mice (4-week-old, female) were subcutaneously injected with MCF-7 cells (5×10⁶ cells/mouse) into the right flank. When tumors reached ~100 mm³, mice were randomized into control (n = 6) and AZD8835 treatment (n = 6) groups. The drug was dissolved in 0.5% carboxymethylcellulose (CMC) + 0.1% Tween 80, administered orally at 10 mg/kg once daily for 21 days. Tumor volume (length×width²/2) and body weight were measured every 3 days; tumors were excised for immunohistochemistry and Western blot [1] - Colon cancer xenograft model: Nude mice (4-week-old, male) were subcutaneously injected with HCT116 cells (5×10⁶ cells/mouse). When tumors reached ~120 mm³, mice were divided into control (n = 6) and treatment (n = 6) groups. AZD8835 was administered orally at 15 mg/kg once daily for 28 days. Survival time was recorded, and tumor tissues were analyzed for angiogenesis (CD31 staining) [1] - Acute inflammation rat model: Male Sprague-Dawley rats (250–300 g) were injected with carrageenan (1% w/v, 0.1 mL) into the hind paw to induce edema. AZD8835 was dissolved in DMSO (5%) + saline (95%), administered orally at 5 mg/kg 1 hour post-carrageenan injection. Paw volume was measured at 0, 2, 4, 6 hours post-drug administration; serum was collected for cytokine analysis [2] - Pharmacokinetic study: Male Sprague-Dawley rats (250–300 g) and beagle dogs (8–10 kg) were administered AZD8835 via oral gavage (10 mg/kg) or intravenous injection (2 mg/kg). Blood samples were collected at multiple time points, and plasma drug concentrations were measured by LC-MS/MS. Pharmacokinetic parameters (Cmax, AUC, t1/2, F) were calculated using non-compartmental analysis [2] |
| ADME/Pharmacokinetics |
Oral bioavailability: 70% in rats and 75% in dogs [2] - Plasma half-life (t1/2): 4.2 hours in rats and 8.5 hours in dogs [2] - Plasma protein binding: 92% in human plasma, 90% in rat plasma, and 93% in dog plasma (equilibrium dialysis method) [2] - Tissue distribution: In rats, the highest concentrations were found in the liver (3.0 times that of plasma), kidney (2.7 times that of plasma), and tumor tissue (2.3 times that of plasma); the permeability to the central nervous system was extremely low (<1.5% of plasma concentration) [2] - Metabolism: Mainly oxidative metabolism mediated by hepatic CYP3A4 and CYP2C9; the main metabolites were hydroxylated derivatives (inactive) [2] - Excretion: In rats, 57% was excreted in feces within 72 hours after administration, and 33% was excreted in feces. Excreted in urine [2]
|
| Toxicity/Toxicokinetics |
In vitro toxicity: AZD8835 at concentrations up to 10 μM showed no significant cytotoxicity to normal human mammary epithelial cells (HMEC) or peripheral blood mononuclear cells (PBMC) (cell viability >85% vs. control group) [1,2]
- Acute toxicity: LD50 in rats and mice >2000 mg/kg (oral administration); no death or serious toxic symptoms (drowsiness, convulsions) were observed at doses up to 2000 mg/kg [1] - Repeat-dose toxicity: In a 28-day rat study (oral doses of 5, 15, and 50 mg/kg/day, respectively), the drug was well tolerated. Mild gastrointestinal discomfort (transient soft stools) was observed only at a dose of 50 mg/kg. No changes in body weight, hematological parameters, or serum biochemical markers (ALT, AST, BUN, creatinine) were detected. Histological examination of major organs revealed no abnormal lesions [1] - Drug interaction potential: AZD8835 does not inhibit or induce major CYP450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4) at therapeutic concentrations [2] |
| References | |
| Additional Infomation |
AZD8835, a PI3Kα inhibitor, is a highly bioavailable, orally bioavailable class I phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) catalytic subunit α (PIK3CA) inhibitor with potential antitumor activity. AZD8835 selectively binds to and inhibits PIK3CA and its mutants in the PI3K/Akt (protein kinase B)/mammalian target of rapamycin (mTOR) pathway. This leads to apoptosis in PIK3CA-expressing tumor cells and inhibits their growth. Because this drug specifically targets PIK3CA, it may be more effective and less toxic than pan-PI3K inhibitors. PI3K/Akt/mTOR pathway dysregulation is common in solid tumors and contributes to tumor cell growth, survival, and resistance to chemotherapy and radiotherapy. PIK3CA is one of the most commonly mutated oncogenes, encoding the p110-α catalytic subunit of class I PI3K.
AZD8835 is a potent, orally bioavailable, and selective class I PI3K inhibitor with preferential activity against PI3Kα and PI3Kδ [1,2]. Its mechanism of action includes inhibiting PI3K-mediated AKT activation, leading to cell cycle arrest and apoptosis in PI3K-dysregulated cancer cells, and inhibiting the production of pro-inflammatory cytokines in immune cells [1,2]. It has shown preclinical efficacy in breast cancer, colon cancer, and inflammatory models, supporting its potential therapeutic applications in solid tumors and inflammatory diseases [1,2]. Its good oral bioavailability, metabolic stability, and low toxicity make it suitable for oral administration in clinical settings [2]. Preclinical studies evaluating it for cancer treatment have focused on tumors dependent on the PI3Kα/δ signaling pathway [1]. |
| Molecular Formula |
C22H31N9O3
|
|---|---|
| Molecular Weight |
469.54
|
| Exact Mass |
469.254
|
| Elemental Analysis |
C, 56.28; H, 6.65; N, 26.85; O, 10.22
|
| CAS # |
1620576-64-8
|
| Related CAS # |
1620576-64-8
|
| PubChem CID |
76685059
|
| Appearance |
Light yellow to yellow solid powder
|
| Density |
1.5±0.1 g/cm3
|
| Boiling Point |
784.0±70.0 °C at 760 mmHg
|
| Flash Point |
427.9±35.7 °C
|
| Vapour Pressure |
0.0±2.9 mmHg at 25°C
|
| Index of Refraction |
1.703
|
| LogP |
3.33
|
| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
10
|
| Rotatable Bond Count |
7
|
| Heavy Atom Count |
34
|
| Complexity |
685
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
CC(C1OC(C2=C(N)N=CC(C3N(N=C(N=3)C3CCN(C(=O)CCO)CC3)CC)=N2)=NN=1)(C)C
|
| InChi Key |
ZGRDYKFVDCFJCZ-UHFFFAOYSA-N
|
| 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)
|
| 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
|
| Synonyms |
AZD-8835; AZD 8835; AZD8835
|
| HS Tariff Code |
2934.99.9001
|
| 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)
|
| Solubility (In Vitro) |
DMSO: ~93 mg/mL (~198.1 mM)
Water: <1 mg/mL Ethanol: <1 mg/mL |
|---|---|
| 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 |
|
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
COA
