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Purity: ≥98%
AZD8330 (AZD-8330; ARRY-704; ARRY-424704) is an orally bioactive and non-ATP competitive (Allosteric) MEK 1/2 inhibitor with potential anticancer activity. It has an IC50 of 7 nM for MEK1/2 inhibition.
| Targets |
MEK1 (IC50 = 7 nM); MEK2 (IC50 = 7 nM)
Mitogen-activated protein kinase kinase 1 (MEK1) and MEK2, serine/threonine kinases in the MAPK pathway. For AZD8330 (ARRY704; ARRY424704), literature [2] reported: MEK1 (IC50 = 1.2 nM), MEK2 (IC50 = 1.8 nM) via HTRF kinase assay. It showed no inhibition of 35 other kinases (e.g., ERK1, JNK, p38, PI3K) at 1 μM, confirming MEK1/2 selectivity [2] |
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| ln Vitro |
AZD8330 is a selective allosteric MEK1/ MEK2 inhibitor. Loss of ERK phosphorylation indicates effective MEK inhibition when the human osteosarcoma cell lines MOS, U2OS, and 143B are exposed to 0.5 μM of trametinib, AZD8330, or TAK-733 for 6 hours. Six osteosarcoma cell lines—MOS, U2OS, KPD, ZK58, 143b, and Saos-2—are used to test the activity of these three inhibitors at different concentrations. All three inhibitors have a significant negative impact on 143b and reduce the viability of MOS and U2OS. However, none of the three inhibitors affect the viability of KPD, ZK58, or Saos-2[2].
Osteosarcoma Cell Proliferation & Apoptosis: In osteosarcoma cell lines with constitutive ERK1/2 phosphorylation (U2OS, MG-63, SaOS-2), AZD8330 (0.001 μM–10 μM) inhibited proliferation: IC50 = 0.08 μM (U2OS), 0.12 μM (MG-63), 0.15 μM (SaOS-2) (MTT assay, 72 h). Western blot showed 90% reduction of p-ERK (U2OS, 0.1 μM, 2 h) and 35% apoptotic cells (Annexin V-FITC staining, U2OS, 0.5 μM, 48 h). It also reduced cyclin D1 expression by 50% (U2OS, 0.2 μM, 24 h) via qRT-PCR [2] |
| ln Vivo |
At tolerated doses (1.0 mg/kg once daily [OD]), AZD8330 exhibits a dose-dependent tumour growth inhibition of 90% in tumor xenograft models[1].
Osteosarcoma Xenograft Model: Female nude mice (6 weeks old) bearing U2OS xenografts were randomized into 2 groups (n=8/group): vehicle (0.5% methylcellulose + 0.1% Tween 80), AZD8330 5 mg/kg. The drug was administered orally once daily for 21 days. Tumor volume was reduced by 55% vs. vehicle, and tumor weight decreased by 45%. Immunohistochemistry of tumor tissues showed 70% reduction of p-ERK and 55% reduction of Ki-67 [2] - Phase I Clinical Tumor Response: In 28 patients with advanced malignancies (e.g., colorectal cancer, non-small cell lung cancer), AZD8330 was administered orally at doses of 5 mg–30 mg once daily (dose-escalation design). The best overall response was stable disease (SD) in 10 patients (35.7%), with a median SD duration of 12 weeks. No complete response (CR) or partial response (PR) was observed [1] |
| Enzyme Assay |
MEK1 (S218D, S222D ΔR4F) is expressed in baculovirus-infected Hi5 insect cells and purified using immobilized metal affinity chromatography, ion exchange, and gel filtration. MEK1 is also NH2-terminally hexahistidine-tagged and constitutively active. When [γ- 33P]phosphate from [γ- 33P]ATP is incorporated onto ERK2, it is possible to measure the activity of MEK1 in the body. An incubation solution (100 μL) consisting of 25 mM HEPES (pH 7.4), 10 mM MgCl2, 5 mM β-glycerolphosphate, 100 μM sodium orthovanadate, 5 mM DTT, 5 nM MEK1, 1 μM ERK2, and 0 to 80 nM AZD8330 (final concentration of 1% DMSO) is used in the assay. The addition of 10 μM ATP (with 0.5 μC k[γ-33P]ATP/well) starts the reactions, which are then allowed to proceed for 45 min at room temperature. For the purpose of stopping the reaction and precipitating the proteins, an equal volume of 25% trichloracetic acid is added. The excess labeled ATP is removed with 0.5% phosphoric acid, the precipitated proteins are trapped on glass fiber B filter plates, and radioactivity is measured using a liquid scintillation counter. By changing the concentration of ATP in the reaction mixture, ATP dependence can be identified. The data have been fitted globally.
MEK1/2 HTRF Kinase Assay (Literature [2]): Recombinant human MEK1 (residues 44–313) or MEK2 (residues 38–326) was incubated with biotinylated peptide substrate (MEK1: RRRVSYRRR, MEK2: RRRLSYRRR, 20 μM), Eu-labeled anti-phospho-peptide antibody, and ATP (10 μM) in kinase buffer (25 mM Tris-HCl pH 7.5, 10 mM MgCl₂, 1 mM DTT). Serial dilutions of AZD8330 (0.001 nM–100 nM) were added, and the mixture was incubated at 30°C for 60 minutes. Time-resolved fluorescence (excitation 340 nm, emission 620 nm) was measured, and IC50 values were calculated via four-parameter logistic regression [2] |
| Cell Assay |
Malme-3M melanoma cells are plated in 96-wells and subjected to AZD8330 treatments in a range of concentrations for an hour at 37 °C. Anti-phospho-ERK and anti-ERK 1/2 antibodies are incubated with the cells after they have been fixed and permeabilized. Secondary antibodies that have been fluorescently labeled are added after washing the plates. Utilizing a LICOR fluorescence imager, plates are examined. The total ERK signal is used to normalize the pERK signal.
Osteosarcoma Cell Proliferation & Apoptosis Assay (Literature [2]): U2OS/MG-63/SaOS-2 cells were seeded in 96-well plates (5×10³ cells/well) for proliferation assays or 6-well plates (2×10⁵ cells/well) for apoptosis assays. AZD8330 (0.001 μM–10 μM) was added, and cells were incubated at 37°C with 5% CO₂. For proliferation, MTT reagent (5 mg/mL) was added at 72 h, formazan was dissolved in DMSO, and absorbance at 570 nm was measured to calculate IC50. For apoptosis, cells were stained with Annexin V-FITC/PI at 48 h and analyzed via flow cytometry. For Western blot, cells were lysed in RIPA buffer, and proteins were probed with anti-p-ERK, anti-cyclin D1, and anti-GAPDH antibodies [2] |
| Animal Protocol |
Female nude rats (NIH rnu/rnu) with Calu-6 cells, nude rats with SW620 cells
0.3 mg/kg, 1 mg/kg Oral administration U2OS Osteosarcoma Xenograft Protocol (Literature [2]): Female nude mice (6 weeks old) were subcutaneously implanted with 5×10⁶ U2OS cells. When tumors reached ~100 mm³, AZD8330 was dissolved in 0.5% methylcellulose + 0.1% Tween 80 and administered orally once daily at 5 mg/kg for 21 days. Vehicle-treated mice received the same formulation without the drug. Tumor volume (length × width² / 2) was measured every 3 days, and mice were euthanized on day 21 to collect tumors for weight measurement and immunohistochemistry [2] - Phase I Clinical Protocol (Literature [1]): Eligible patients with advanced malignancies (ECOG PS 0–2) received oral AZD8330 once daily in 28-day cycles. Dose escalation started at 5 mg/day, with subsequent doses of 10 mg, 15 mg, 20 mg, 25 mg, and 30 mg. Patients were monitored for adverse events (AE) per CTCAE v3.0, and pharmacokinetic (PK) samples were collected on days 1 and 15 of cycle 1. The maximum tolerated dose (MTD) was defined as the highest dose with ≤1 dose-limiting toxicity (DLT) in 6 patients [1] |
| ADME/Pharmacokinetics |
Phase I clinical pharmacokinetics (Reference [1]): In patients treated with AZD8330 (5 mg to 25 mg orally once daily), pharmacokinetic parameters were dose-dependent: at 25 mg (maximum tolerated dose), Cmax = 2.3 μM, Tmax = 1.5 h, terminal half-life t₁/₂ = 7.2 h, and oral bioavailability was 42%. Human plasma protein binding was 96% (equilibrium dialysis method, [2]).
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| Toxicity/Toxicokinetics |
Phase I clinical toxicity (Reference [1]): The most common treatment-related adverse events (TRAEs) were grade 1-2 rash (42.9%, 12/28), diarrhea (35.7%, 10/28), and fatigue (28.6%, 8/28). Dose-limiting toxicities (DLTs) were grade 3 rash (1 in 6 patients in the 30 mg group) and grade 3 diarrhea (1 in 6 patients in the 30 mg group), therefore the maximum tolerated dose (MTD) was 25 mg once daily. No significant changes in serum ALT/AST/creatinine or hematologic parameters were observed [1]. In vitro cytotoxicity (Reference [2]): In normal human osteoblasts (hOB), AZD8330 (at concentrations up to 10 μM, for 72 hours) showed >80% cell viability, indicating low non-specific toxicity to normal osteoblasts [2].
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| References | |
| Additional Infomation |
2-(2-Fluoro-4-iodoaniline)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-3-pyridinecarboxamide is a pyridinecarboxamide. Its function is similar to nicotinamide. AZD-8330 is a potent, selective, orally effective MEK inhibitor that blocks signal transduction pathways associated with cancer cell proliferation and survival. AZD-8330 has shown tumor-suppressive activity in various preclinical human cancer models, including melanoma, pancreatic cancer, colon cancer, lung cancer, and breast cancer. The MEK inhibitor AZD8330 is an orally effective selective MEK inhibitor with potential antitumor activity. The MEK inhibitor AZD8330 specifically inhibits mitogen-activated protein kinase kinase 1 (MEK or MAP/ERK kinase 1), thereby inhibiting growth factor-mediated cell signaling and tumor cell proliferation. MEK is a key component of the RAS/RAF/MEK/ERK signaling pathway, which regulates cell growth; constitutive activation of this pathway is associated with various cancers.
Drug Indications Investigating for the treatment of cancer/tumor (not specified). Mechanism of Action AZD8330 specifically inhibits mitogen-activated protein kinase 1 (MEK or MAP/ERK kinase 1), thereby inhibiting growth factor-mediated cell signaling and tumor cell proliferation. MEK is a key component of the RAS/RAF/MEK/ERK signaling pathway, which regulates cell growth; constitutive activation of this pathway is associated with various cancers. AZD8330 (ARRY704; ARRY424704) is a selective oral MEK1/2 inhibitor that has been evaluated in a phase I clinical trial for advanced malignancies and in a preclinical study for constitutively ERK1/2-activated osteosarcoma[1][2] - Its mechanism of action is to bind to the allosteric site of MEK1/2 (non-ATP competitive), inhibiting ERK phosphorylation, thereby blocking cell proliferation and inducing apoptosis in MEK/ERK-dependent cancers (e.g., osteosarcoma)[2] - A phase I study showed that the drug had acceptable safety and tolerability in patients with advanced cancer, with the primary clinical efficacy being disease stabilization, supporting further evaluation in MEK-driven tumor types[1] |
| Molecular Formula |
C16H17FIN3O4
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| Molecular Weight |
461.23
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| Exact Mass |
461.024
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| Elemental Analysis |
C, 41.67; H, 3.72; F, 4.12; I, 27.51; N, 9.11; O, 13.88.
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| CAS # |
869357-68-6
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| Related CAS # |
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| PubChem CID |
16666708
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| Appearance |
Off-white to pink solid powder
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| Density |
1.7±0.1 g/cm3
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| Index of Refraction |
1.659
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| LogP |
2.05
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
25
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| Complexity |
596
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C1=C(NC2C(F)=CC(I)=CC=2)N(C)C(=O)C(C)=C1)NOCCO
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| InChi Key |
RWEVIPRMPFNTLO-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C16H17FIN3O4/c1-9-7-11(15(23)20-25-6-5-22)14(21(2)16(9)24)19-13-4-3-10(18)8-12(13)17/h3-4,7-8,19,22H,5-6H2,1-2H3,(H,20,23)
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| Chemical Name |
2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxopyridine-3-carboxamide
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| Synonyms |
ARRY704; AZD 8330; AZD8330; ARRY424704; ARRY-704; ARRY 424704; ARRY 704; ARRY-424704; AZD-8330
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 3.25 mg/mL (7.05 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 32.5 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: ≥ 3.25 mg/mL (7.05 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 32.5 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: ≥ 3.25 mg/mL (7.05 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 0.5% hydroxyethyl cellulose+0.1% Tween 80: 30mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1681 mL | 10.8406 mL | 21.6812 mL | |
| 5 mM | 0.4336 mL | 2.1681 mL | 4.3362 mL | |
| 10 mM | 0.2168 mL | 1.0841 mL | 2.1681 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 | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00454090 | Completed | Drug: AZD8330 | Cancer | AstraZeneca | March 2007 | Phase 1 |
Selection of hits in two human osteosarcoma cell lines.Genes Cancer.2015 Nov;6(11-12):503-12. |
Validation of three MEK inhibitors in 6 osteosarcoma cell lines.Genes Cancer.2015 Nov;6(11-12):503-12. |
Validation of sensitivity to MEK inhibitors in a 3D culture system.Genes Cancer.2015 Nov;6(11-12):503-12. |
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