| Size | Price | Stock | Qty |
|---|---|---|---|
| 25mg |
|
||
| 50mg |
|
||
| 100mg |
|
||
| 250mg |
|
||
| 500mg | |||
| Other Sizes |
Purity: ≥98%
Avitinib maleate (formerly also known as AC-0010, AC0010MA; Abivertinib), the maleate salt of avitinib, is an orally bioavailable and covalent/irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor selective for T790M resistance mutations. It has anticancer activity and currently in clinical trials. AC0010 is a pyrrolopyrimidine-based irreversible EGFR inhibitor, structurally distinct from previously reported pyrimidine-based irreversible EGFR inhibitors, such as osimertinib and rociletinib.
| Targets |
Epidermal Growth Factor Receptor (EGFR) (mutated EGFR, T790M-mutated EGFR; 298-fold more potent than wild-type EGFR) [1]
Bruton Tyrosine Kinase (BTK) [2] |
|---|---|
| ln Vitro |
In NCI-H1975 and NIH/3T3_TC32T8 cells, avitinib (AC0010; 0.13 nM-2 μM; 2 h) maleate selectively inhibits the phosphorylation of mutant EGFR with IC50 values of 7.3 and 2.8 nM, respectively. These values are approximately 115 and 298 times more sensitive than inhibition. EGFR times wild-type in A431. In NCI-H1975 cells, avitinib efficiently inhibits EGFR-Tyr1068 phosphorylation, and NCI-H1975 cells have 65 times greater selectivity than A431 cells. Apart from preventing EGFR-Tyr1068 phosphorylation, avitinib also prevents Akt and ERK1/2, which are downstream targets, from becoming phosphorylated in NCI-H1975 and HCC827 cells [1].
Avitinib (AC0010) maleate is an irreversible EGFR inhibitor that selectively inhibits active-mutated EGFR and T790M-mutated EGFR, with a potency up to 298-fold higher than that against wild-type EGFR [1] - Its three major metabolites show no inhibitory activity against wild-type EGFR or off-target effects such as inhibition of IGF-1R [1] - Compared with ibrutinib, it exhibits stronger toxicity to mantle cell lymphoma (MCL) cell lines (Jeko-1, JVM-2) and primary MCL cells in vitro (p < 0.01), without increasing cytotoxicity to normal peripheral lymphocytes [2] - It induces significant apoptosis in MCL cell lines (p < 0.01) through the caspase family and Bcl-2 family proteins; Western blot shows changes in the expression of caspase-3, PARP, Bcl-2, Bcl-xl, Bax, and Bim [2] - It inhibits the phosphorylation of BTK (Tyr223) in MCL cells, thereby suppressing the BCR-BTK signaling pathway (downregulating p-PLCγ2, p-IKKα/β, NF-κBp-65, p-NF-κBp-65, ERK, p-ERK, and Ras) and the PI3K/AKT signaling pathway (downregulating PI3K, AKT, p-AKT, GSK3β, and np-GSK3β) [2] - q-PCR and Western blot analyses show that BTK mRNA expression is slightly affected, while BTK protein is slightly downregulated and p-BTK is significantly downregulated in MCL cells after treatment [2] - Flow cytometry analysis reveals its regulatory effect on the cell cycle of MCL cell lines [2] - After treating MCL cells with Avitinib (AC0010) maleate for 1 hour and washing it out, stimulation with anti-IgG for 2 minutes results in reduced p-BTK expression as detected by Western blot [2] |
| ln Vivo |
In xenograft models, long-term avitinib (AC0010; 12.5-500 mg/kg; oral; once daily; for 14 days) slows the growth of EGFR mutant tumors but not wild-type EGFR tumors [1].
In xenograft models bearing tumors with active-mutated EGFR and T790M-mutated EGFR, oral administration of Avitinib (AC0010) maleate at a daily dose of 500 mg/kg achieves complete tumor remission for over 143 days without weight loss [1] - In non-small cell lung cancer (NSCLC) patients, doses ranging from 50 mg to 550 mg once daily are safe, with no hyperglycemia or severe adverse effects such as grade 3 QT prolongation; objective responses are observed in NSCLC patients with EGFR T790M mutation [1] - In MCL xenograft models using SCID mice, Avitinib (AC0010) maleate at a dose of 300 mg/kg significantly prolongs the survival rate of mice (p < 0.01) [2] |
| Cell Assay |
Western Blot Analysis[1]
Cell Types: NCI-H1975, HCC827, A431 cells Tested Concentrations: 0.13 nM, 0.64 nM, 3.2 nM, 16 nM, 80 nM, 0.4 μM, 2 μM Incubation Duration: 2 h Experimental Results: Selectively inhibits mutant EGFR phosphorylation with IC50 values of 7.3 and 2.8 nM in NCI-H1975 and NIH/3T3_TC32T8 cells. Growth inhibition assay: MTS assay is used to detect the growth inhibitory effects of Avitinib (AC0010) maleate and ibrutinib on MCL cell lines (Jeko-1, JVM-2), primary MCL cells, and normal peripheral lymphocytes [2] - Apoptosis assay: Flow cytometry is performed to detect the apoptosis of Jeko-1 and JVM-2 cells after treatment with Avitinib (AC0010) maleate; Western blot is used to analyze the expression of apoptosis-related proteins including caspase family and Bcl-2 family [2] - Gene and protein expression assay: q-PCR and Western blot are applied to examine the mRNA and protein expression levels of BTK and p-BTK, as well as the expression of proteins in BTK-related signaling pathways [2] - Cell cycle assay: Flow cytometry is used to detect the effect of Avitinib (AC0010) maleate on the cell cycle of MCL cell lines [2] - BTK phosphorylation assay: MCL cells are treated with Avitinib (AC0010) maleate for 1 hour, then the drug is washed out; the cells are stimulated with anti-IgG for 2 minutes, and the expression of p-BTK is detected by Western blot [2] |
| Animal Protocol |
Animal/Disease Models: Nu/Nu nude mice (Six- to 8weeks old) injected with NCI-H1975 and A431 cells[1]
Doses: 12.5, 50, and 500 mg/kg Route of Administration: Orally administration; one time/day; for 14 days Experimental Results: Inhibited EGFR-mutant tumor growth but not wild-type EGFR tumor growth. EGFR-mutated tumor xenograft model: Mice bearing xenografts with active-mutated EGFR and T790M-mutated EGFR are given Avitinib (AC0010) maleate orally at a daily dose of 500 mg/kg. Tumor remission and body weight changes are monitored for over 143 days [1] - NSCLC clinical trial: NSCLC patients are administered Avitinib (AC0010) maleate at doses ranging from 50 mg to 550 mg once daily. Safety indicators (such as hyperglycemia, QT interval) and objective responses are evaluated [1] - MCL xenograft model: SCID mice bearing MCL xenografts are treated with Avitinib (AC0010) maleate at a dose of 300 mg/kg. The survival rate of mice is observed and recorded [2] |
| Toxicity/Toxicokinetics |
In patients with non-small cell lung cancer (NSCLC), acitinib maleate (AC0010) administered once daily at doses of 50–550 mg is safe and does not cause hyperglycemia or serious adverse reactions such as grade 3 QT prolongation [1]. In animal models, a daily oral dose of 500 mg/kg does not result in weight loss [1]. Compared with ibrutinib, it does not increase cytotoxicity against normal peripheral lymphocytes [2].
|
| References |
|
| Additional Infomation |
Abivitinib maleate is the maleate salt form of arbivitinib, an orally effective, irreversible, mutant-selective inhibitor of epidermal growth factor receptor (EGFR) with potential antitumor activity. After oral administration, arbivitinib covalently binds to and inhibits the activity of EGFR mutants, including the resistant T790M EGFR mutant, thereby blocking EGFR mutant-mediated signaling. This may induce death in EGFR-mutant tumor cells and inhibit tumor growth. EGFR is a receptor tyrosine kinase that is mutated in various cancers and plays a crucial role in tumor cell proliferation and tumor angiogenesis. Due to its selectivity for EGFR mutants, this drug may have reduced toxicity compared to non-selective EGFR inhibitors, which also inhibit wild-type EGFR. After oral administration, arbivitinib covalently binds to and inhibits the activity of EGFR mutants (including the resistant T790M EGFR mutant), thereby blocking EGFR mutant-mediated signaling. This may induce death in EGFR-mutant tumor cells and inhibit tumor growth. EGFR is a receptor tyrosine kinase that is mutated in various cancers and plays a crucial role in tumor cell proliferation and tumor angiogenesis. Because this drug is selective for EGFR mutants, its toxicity may be reduced compared to non-selective EGFR inhibitors, which also inhibit wild-type EGFR.
Avitinib maleate (AC0010) is a pyrrolopyrimidine irreversible EGFR inhibitor with a structure different from previously reported pyrimidine irreversible EGFR inhibitors such as osimertinib and roxitinib[1] - It can overcome T790M-induced resistance in EGFR-mutant non-small cell lung cancer (NSCLC)[1] - As a novel BTK inhibitor, it has shown good efficacy and safety compared to ibrutinib in the treatment of mantle cell lymphoma (MCL)[2] - Its anti-MCL mechanism involves the inhibition of the BCR-BTK and PI3K/AKT signaling pathways[2] |
| Molecular Formula |
C30H30FN7O6
|
|
|---|---|---|
| Molecular Weight |
603.61
|
|
| Exact Mass |
603.224
|
|
| CAS # |
1557268-88-8
|
|
| Related CAS # |
Avitinib;1557267-42-1
|
|
| PubChem CID |
121596128
|
|
| Appearance |
Light yellow to yellow solid powder
|
|
| Hydrogen Bond Donor Count |
5
|
|
| Hydrogen Bond Acceptor Count |
12
|
|
| Rotatable Bond Count |
9
|
|
| Heavy Atom Count |
44
|
|
| Complexity |
871
|
|
| Defined Atom Stereocenter Count |
0
|
|
| SMILES |
CN1CCN(CC1)C2=C(C=C(C=C2)NC3=NC4=C(C=CN4)C(=N3)OC5=CC=CC(=C5)NC(=O)C=C)F.C(=C\C(=O)O)\C(=O)O
|
|
| InChi Key |
VRHPZWLHPIENFW-BTJKTKAUSA-N
|
|
| InChi Code |
InChI=1S/C26H26FN7O2.C4H4O4/c1-3-23(35)29-17-5-4-6-19(15-17)36-25-20-9-10-28-24(20)31-26(32-25)30-18-7-8-22(21(27)16-18)34-13-11-33(2)12-14-34;5-3(6)1-2-4(7)8/h3-10,15-16H,1,11-14H2,2H3,(H,29,35)(H2,28,30,31,32);1-2H,(H,5,6)(H,7,8)/b;2-1-
|
|
| Chemical Name |
|
|
| Synonyms |
|
|
| 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 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)
|
| Solubility (In Vitro) |
|
|||
|---|---|---|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.14 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 (4.14 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (4.14 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 | 1.6567 mL | 8.2835 mL | 16.5670 mL | |
| 5 mM | 0.3313 mL | 1.6567 mL | 3.3134 mL | |
| 10 mM | 0.1657 mL | 0.8283 mL | 1.6567 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.
Response of NSCLC patients with T790M-acquired mutations to AC0010 treatment and their AC0010 plasma concentrations. |
|---|
Inhibition of cell proliferation and EGFR phosphorylation.Mol Cancer Ther.2016 Nov;15(11):2586-2597. |
In vivoantitumor efficacy and pharmacokinetics/pharmacodynamics in xenograft models.Mol Cancer Ther.2016 Nov;15(11):2586-2597. |
Proposed AC0010 metabolic pathways and activities of its major metabolites.Mol Cancer Ther.2016 Nov;15(11):2586-2597. |
|---|
 AC0010 chemical structure and T790M EGFR-binding modes.Mol Cancer Ther.2016 Nov;15(11):2586-2597. |
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
COA
