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Purity: ≥98%
AZD-3463 (AZD3463) is a novel, potent and selective ALK/IGF1R inhibitor with potential anticancer activity. It is capable of overcoming several ways in which crizotinib-induced acquired resistance occurs. By causing apoptosis and overcoming crizotinib resistance, AZD3463 prevents the growth of neuroblastomas. In orthotopic xenograft mouse models, AZD3463 demonstrated a strong antitumor efficacy against neuroblastoma tumors containing WT and F1174L oncogenic mutant ALK.
| Targets |
IGF-1R; ALK (Ki = 0.75 nM)
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|---|---|
| ln Vitro |
AZD3463 exhibits strong effects in preclinical models driven by ALK as well as in a range of crizotinib-resistant models. As evidenced by its capacity to reduce ALK autophosphorylation in tumor cell lines carrying ALK fusions, such as DEL (ALCL NPM-ALK), H3122 (NSCLC EML4-ALK), and H2228 (NSCLC EML4-ALK), AZD3463 inhibits ALK in cells. ALK inhibition is linked to disruptions in the ERK, AKT, and STAT3 signaling cascades, which specifically inhibit the proliferation of ALK-fusion-containing cell lines in vitro. AZD3463 continues to exhibit strong activity against several clinically significant crizotinib-resistant mutations, such as the gatekeeper mutant L1196M, which exhibits in vitro and in vivo equivalent potency to wild type ALK in BAF3 cell lines containing EML4-ALK. In order to evaluate AZD3463's potential to circumvent additional resistance mechanisms, antiproliferative activity is evaluated in both a patient-derived crizotinib relapsed model and multiple independently derived in vitro crizotinib resistant cell lines derived from H3122 cells. The L1196M gatekeeper and T115Ins mutations, ALK amplification, and/or secondary drivers like EGFR and IGF1R are just a few of the resistance mechanisms present in these resistant cell lines. In vitro, AZD3463 maintains its antiproliferative efficacy in 10 of the 12 acquired resistance models, four times that of the parental H3122 cells.[1]
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| ln Vivo |
AZD3463 exhibits the capacity to inhibit pALK in xenograft tumors in vivo in a dose-dependent manner, leading to either stasis (H3122) or regression (DEL, H2228).[1]
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| Enzyme Assay |
ZD-3463 is an ALK/IGF1R inhibitor that circumvents a number of mechanisms involved in the development of crizotinib resistance.
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| Animal Protocol |
5 to 6-week-old female athymic Ncr nude mice (SH-SY5Y and NGP xenograft tumors bearing mice)[1].
15 mg/kg Intraperitoneal injection; once daily for 2 days |
| References | |
| Additional Infomation |
AZD3463 is a member of the class of indoles that is 1H-indole substituted by a 2-[4-(4-aminopiperidin-1-yl)-2-methoxyanilino]-5-chloropyrimidin-4-yl group at position 3. It is an orally bioavailable dual inhibitor of ALK and IGF1R with Ki value of 0.75 nM for ALK. It has a role as an apoptosis inducer, an antineoplastic agent, an EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor and an autophagy inducer. It is a member of indoles, an aminopiperidine, a monomethoxybenzene, an aminopyrimidine, a secondary amino compound, a tertiary amino compound and an organochlorine compound.
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| Molecular Formula |
C24H25CLN6O
|
|---|---|
| Molecular Weight |
448.9479
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| Exact Mass |
448.177
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| Elemental Analysis |
C, 64.21; H, 5.61; Cl, 7.90; N, 18.72; O, 3.56
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| CAS # |
1356962-20-3
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| Related CAS # |
1356962-20-3
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| PubChem CID |
56599293
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| Appearance |
Light green to green solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
723.6±70.0 °C at 760 mmHg
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| Flash Point |
391.4±35.7 °C
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| Vapour Pressure |
0.0±2.3 mmHg at 25°C
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| Index of Refraction |
1.693
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| LogP |
3.11
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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 |
5
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| Heavy Atom Count |
32
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| Complexity |
605
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC(C=NC(NC1=C(OC)C=C(N2CCC(N)CC2)C=C1)=N3)=C3C4=CNC5=C4C=CC=C5
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| InChi Key |
GCYIGMXOIWJGBU-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H25ClN6O/c1-32-22-12-16(31-10-8-15(26)9-11-31)6-7-21(22)29-24-28-14-19(25)23(30-24)18-13-27-20-5-3-2-4-17(18)20/h2-7,12-15,27H,8-11,26H2,1H3,(H,28,29,30)
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| Chemical Name |
N-[4-(4-aminopiperidin-1-yl)-2-methoxyphenyl]-5-chloro-4-(1H-indol-3-yl)pyrimidin-2-amine
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| Synonyms |
AZD 3463; AZD-3463; AZD3463
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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: 6~20 mg/mL (13.4~44.6 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2 mg/mL (4.45 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 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 20.0 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2274 mL | 11.1371 mL | 22.2742 mL | |
| 5 mM | 0.4455 mL | 2.2274 mL | 4.4548 mL | |
| 10 mM | 0.2227 mL | 1.1137 mL | 2.2274 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.
 AZD3463 shows cytotoxic effects on NB cell lines.Sci Rep.2016Jan 20;6:19423. |
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 AZD3463 suppresses anchorage-independent growth of NB cells.Sci Rep.2016Jan 20;6:19423. |
 AZD3463 enhances the cytotoxic effect of Dox on NB cell lines.Sci Rep.2016Jan 20;6:19423. |
 AZD3463 inhibits tumor growth in different orthotopic NB xenograft mouse models.Sci Rep.2016Jan 20;6:19423. |
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 AZD3463 inhibits the downstream signaling pathway of ALK, PI3K/AKT/mTOR, and induces apoptosis and autophagy in NB cells.IMR-32, NGP, SH-SY5Y and SK-N-AS cells were treated with 10 μM of AZD3463 for various time points (0–4 hrs), subjected to SDS-PAGE, and then immunoblotted with PARP, p-Akt, Akt, p-S6, S6, Caspase 3, LC3A/B, and β-Actin antibodies.Sci Rep.2016Jan 20;6:19423. |
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