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| 5mg |
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Purity: ≥98%
AZ7550 Mesylate (AZ-7550), the mesylate salt of AZ 7550, is an active metabolite of AZD-9291 (Osimertinib) by removing one of the methyl groups from the ethyl diamine side chain. AZD 9291 (Osimertinib) was approved in 2015 for the treatment of non-small-cell lung cancer (NSCLC) in patients harboring sensitizing (or activating) mutations for a number of years.
| Targets |
In terms of potency and selectivity, AZ7550 (compound 28) seems to offer properties that are largely comparable to those of the parent molecule AZD9291. The DM cell line H1975, the AM cell line PC9, and the WT cell line LoVo are all inhibited by AZ7550, with IC50 values of 45, 26, and 786 nM, respectively. The anti-proliferative cell lines H1975 from DM, PC9 from AM, and Calu3 from WT are all inhibited by AZ7550, with GI50 values of 19, 15, and 537 nM, respectively[1].
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| ln Vitro |
In terms of potency and selectivity, AZ7550 (compound 28) seems to offer properties that are largely comparable to those of the parent molecule AZD9291. The DM cell line H1975, the AM cell line PC9, and the WT cell line LoVo are all inhibited by AZ7550, with IC50 values of 45, 26, and 786 nM, respectively. The anti-proliferative cell lines H1975 from DM, PC9 from AM, and Calu3 from WT are all inhibited by AZ7550, with GI50 values of 19, 15, and 537 nM, respectively[1].
In cellular phosphorylation assays, AZD9291 inhibited EGFR phosphorylation in H1975 (DM) cells with an IC₅₀ of 15 nM and in PC9 (AM) cells with an IC₅₀ of 17 nM, demonstrating high potency against mutant EGFR. [1] In antiproliferative assays, AZD9291 showed GI₅₀ values of 24 nM in H1975 (DM) cells, 23 nM in PC9 (AM) cells, and 264 nM in Calu3 (WT) cells, confirming selective growth inhibition of mutant-driven cells. [1] AZD9291 exhibited moderate activity against IGF1R (IC₅₀ = 2.9 µM) and low affinity for the hERG ion channel (IC₅₀ = 16.2 µM). [1] Kinase selectivity profiling (Millipore panel of 270 kinases) showed that AZD9291 had a good overall selectivity profile, with most significant off-target activity against other tyrosine kinases such as IGF1R and INSR. [1] |
| ln Vivo |
In mouse xenograft models, oral administration of AZD9291 at 10 mg/kg/day for 7 days induced significant tumor regression in both H1975 (DM) and PC9 (AM) models, while having minimal effect on the A431 (WT EGFR) model. [1]
At a lower dose of 5 mg/kg/day for 7 days, AZD9291 still showed excellent efficacy in the H1975 and PC9 models. [1] A single oral dose of AZD9291 (10 mg/kg) in mice bearing H1975 or PC9 xenografts led to profound and sustained inhibition of EGFR phosphorylation (p-EGFR) in tumors for up to 24 hours. [1] In a rat toxicology study, a single 200 mg/kg oral dose of AZD9291 did not cause significant changes in blood glucose or insulin levels, in contrast to other candidate compounds which induced hyperglycemia and hyperinsulinemia. [1] |
| Cell Assay |
Cellular Phosphorylation Assay: Cells (e.g., H1975, PC9, Calu3) were treated with compound for 2 hours. Following incubation, cells were lysed, and EGFR phosphorylation levels were measured using ELISA kits. Dose-response curves were generated to calculate IC₅₀ values for inhibition of phosphorylation. [1]
Antiproliferative Assay: Cells were seeded and allowed to adhere. Serial dilutions of the compound were added, and cells were incubated for a specified period (typically several days). Cell viability or growth inhibition was measured using a suitable endpoint assay (e.g., ATP content). GI₅₀ values, representing the concentration causing 50% growth inhibition, were calculated from dose-response curves. [1] |
| Animal Protocol |
Mouse Xenograft Efficacy Studies: Immune-compromised mice were inoculated subcutaneously with human tumor cell lines (H1975, PC9, or A431). Once tumors reached a predetermined volume, mice were randomized into treatment groups. AZD9291 was administered orally once daily (q.d.) as a suspension in 0.5% hydroxypropyl methylcellulose (HPMC) / 0.1% Tween in deionized water. Tumor volumes were measured regularly, and percent tumor growth inhibition (%TGI) or regression was calculated compared to the vehicle control group. [1]
Mouse Pharmacodynamic (PD) Studies: Mice bearing established H1975 or PC9 xenografts received a single oral dose of AZD9291 (e.g., 10 mg/kg) formulated as above. Groups of mice were euthanized at various time points post-dose (e.g., 1, 6, 16, 24, 30 hours). Tumors were excised, homogenized, and analyzed for levels of phosphorylated EGFR (p-EGFR) and total EGFR, typically using ELISA, to determine the percentage inhibition of p-EGFR. [1] Rat Toxicology Study: Rats received a single oral dose of AZD9291 (200 mg/kg) as a suspension in 0.5% HPMC/0.1% Tween. Blood samples were collected over a 24-hour period for measurement of glucose and insulin levels to assess effects on the glucose/insulin axis. [1] Guinea Pig Cardiovascular Safety Study: Compounds were assessed in an in vivo guinea pig model to evaluate effects on hemodynamic, ECG, and contractility parameters, including QT interval prolongation. [1] |
| ADME/Pharmacokinetics |
In rats, the intravenous clearance (CL) of AZD9291 was 45 mL/min/kg, which is low to moderate; the oral bioavailability (F) was low, at 16% at a dose of 5 mg/kg. [1] In mice, the AUC of AZD9291 after oral administration of 10 mg/kg was 1.4 µM·h and the Cmax was 0.38 µM. [1] AZD9291 showed low plasma protein binding in different species: rats (free concentration 16%), humans (free concentration 2.9%) and mice (free concentration 7.5%). [1] The major circulating metabolites of AZD9291 in vivo were identified as demethylated metabolites (27, formed by the loss of indole N-methyl) and side-chain dealkylated products (28). In mice treated with AZD9291, metabolite 27 was present at lower concentrations than the parent drug, but exhibited higher cellular potency and lower protein binding, thereby improving overall efficacy. [1]
Its in vitro intrinsic clearance in rat and human hepatocytes was relatively low (rat: 27 µL/min/10⁶ cells; human: <3 µL/min/10⁶ cells). [1] |
| Toxicity/Toxicokinetics |
In a rat toxicology study, a single oral dose of 200 mg/kg of AZD9291 did not cause significant hyperglycemia or hyperinsulinemia, unlike the control compound. This was attributed to its weaker inhibitory effects on IGF1R and INSR (INSR IC₅₀ = 0.912 µM). [1] In a guinea pig cardiovascular safety model, AZD9291 did not show significant QT interval prolongation at free Cmax concentrations, consistent with its lower hERG channel affinity (IC₅₀ = 16.2 µM) compared to other candidate drugs. [1] The formation of the active metabolite 27 is considered a potential risk factor for wild-type EGFR-driven toxicities (e.g., rash, diarrhea) due to its narrow selectivity for wild-type EGFR. However, early clinical data indicate that it is well-tolerated. [1]
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| References | |
| Additional Infomation |
AZD9291 is a third-generation EGFR TKI designed to overcome resistance mediated by the T790M mutation in non-small cell lung cancer (NSCLC) while minimizing wild-type EGFR-related toxicities. [1] It exerts irreversible inhibitory effects by covalently binding to cysteine residue 797 in the EGFR kinase domain. [1] Due to manufacturing process and physical properties considerations, AZD9291 mesylate, rather than the free base, was selected for clinical development. The pharmacokinetics of the mesylate are comparable to those of the free base. [1] Based on preclinical efficacy and safety data, AZD9291 was selected as a clinical candidate. The initial human dose was set at 20 mg orally once daily. [1]
Preliminary clinical data from a phase I clinical trial (AURA) in patients with EGFR mutation-positive advanced non-small cell lung cancer whose disease had progressed after prior EGFR-TKI treatment showed encouraging tumor response (e.g., tumor shrinkage of approximately 40-60%) and good safety profile, with no serious rash events reported and only mild diarrhea reported. [1] |
| Molecular Formula |
C28H35N7O5S
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|---|---|
| Molecular Weight |
581.686404466629
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| Exact Mass |
773.218
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| CAS # |
2319837-99-3
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| Related CAS # |
AZ7550;1421373-99-0;AZ7550 hydrochloride;2309762-40-9
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| PubChem CID |
134611624
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| Appearance |
Light yellow to yellow solid powder
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| Hydrogen Bond Donor Count |
6
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| Hydrogen Bond Acceptor Count |
16
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| Rotatable Bond Count |
10
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| Heavy Atom Count |
51
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| Complexity |
817
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| Defined Atom Stereocenter Count |
0
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| SMILES |
S(O)(=O)(=O)C.CN1C2=CC=CC=C2C(C2C=CN=C(NC3C=C(NC(=O)C=C)C(N(C)CCNC)=CC=3OC)N=2)=C1
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| InChi Key |
AZRGPJKRGFXCLD-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C27H31N7O2.3CH4O3S/c1-6-26(35)30-21-15-22(25(36-5)16-24(21)33(3)14-13-28-2)32-27-29-12-11-20(31-27)19-17-34(4)23-10-8-7-9-18(19)23;3*1-5(2,3)4/h6-12,15-17,28H,1,13-14H2,2-5H3,(H,30,35)(H,29,31,32);3*1H3,(H,2,3,4)
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| Chemical Name |
methanesulfonic acid;N-[4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]-2-[methyl-[2-(methylamino)ethyl]amino]phenyl]prop-2-enamide
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| Synonyms |
AZ7550 Mesylate; AZ 7550; AZ-7550
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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 : ~25 mg/mL (~32.30 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (3.23 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 25.0 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (3.23 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 25.0 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7191 mL | 8.5956 mL | 17.1913 mL | |
| 5 mM | 0.3438 mL | 1.7191 mL | 3.4383 mL | |
| 10 mM | 0.1719 mL | 0.8596 mL | 1.7191 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.
AZD9291 binding mode and structure.Cancer Discov.2014 Sep;4(9):1046-61. |
Effect of AZD9291 on EGFR phosphorylationin vitro.Cancer Discov.2014 Sep;4(9):1046-61. |
In vivoanti-tumor efficacy of AZD9291 in subcutaneous xenograft models of EGFR-TKI sensitising and T790M resistant lung cancer.Cancer Discov.2014 Sep;4(9):1046-61. |
AZD9291 induces significant and sustained tumor regression in transgenic models of EGFR-TKI sensitising (C/L858R) and T790M resistant (C/L+T) lung cancer.Cancer Discov.2014 Sep;4(9):1046-61. |
AZD9291 inhibits EGFR phosphorylation and downstream signallng in murine models of EGFR T790M resistant lung cancer.Cancer Discov.2014 Sep;4(9):1046-61. |
Proof of concept clinical studies validating AZD9291 as a mutant-selective EGFR kinase T790M inhibitor.Cancer Discov.2014 Sep;4(9):1046-61. |
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