Avitinib (AC0010)

Alias: AC0010; AC-0010MA; AC-0010; AC 0010MA; AC 0010; AC0010MA; Abivertinib

Cat No.:V3696 Purity: ≥98%

COA Product Data Instructions for use SDS

Avitinib (AC0010) Chemical Structure CAS No.: 1557267-42-1
Product category: EGFR

This product is for research use only, not for human use. We do not sell to patients.

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Other Forms of Avitinib (AC0010):

Avitinib (AC0010) maleate

Official Supplier of:

Top Publications Citing lnvivochem Products

Nature 2021, 597(7874):119-125.

Cell 2020,183:1202-1218.e25.

Science Adv 2022: 8, eabm9427.

Nature 597, 119–125 (2021)

Cell Stem Cell 2020,26(6):845-861.e12.

Science Trans Med 2023,15(701):eadd7872.

STTT 2023,8(1):91.

Cell Reports 2023,42(4):112313

Science Trans Med 2023, 15: eadd7872.

Cancer Cell 2021,39(4):529-547.e7.

Cancer Discov 2022,12(4):1106-1127.

Immunity 2023,56(3):620-634.e11.

J Am Chem Soc 2022,144:21831-21836.

Cell 2020,183:1202-1218.e25.

Science Adv 2022:8,eabm9427.

Nature 2021,597(7874):119-125.

Cell 2020,183:1202-1218.e25.

PNAS Nexus 2022,1(3):pgac063.

ACS Nano 2023,17(10):9110-9125.

Biomaterial 2023 Sep16:302:122333.

Purity & Quality Control Documentation

Current batch：

Purity: ≥98%

COA

MSDS

Instructions

Product Description
Bioactivity & Protocols
Physicochemical Properties
Solubility Data
Calculators
Clinical Trial Information
Biological Data

Product Description

Avitinib (Abivertinib, AC-0010, AC-0010MA, AC0010, AC0010MA) is a pyrrolopyrimidine-based, orally bioactive, and irreversible/covalent inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase with selectivity against T790M resistance mutations. Avitinib differs structurally from other known irreversible EGFR inhibitors based on pyrimidines, such as rociletinib and osimertinib.

Biological Activity I Assay Protocols (From Reference)

Targets

EGFR L858R (IC50 = 0.18 nM); EGFR^T790M (IC50 = 0.18 nM); EGFR (WT) (IC50 = 7.68 nM)

ln Vitro

AC0010 selectively and up to 298-fold more potently than wild-type EGFR inhibits T790M mutations and EGFR activity. With IC50 values of 7.3 nM and 2.8 nM, respectively, AC0010 selectively inhibited the phosphorylation of mutant EGFR in NCI-H1975 and NIH/3T3_TC32T8 cells. This was approximately 115- and 298-fold more sensitive than the inhibition of wild type EGFR in A431. The EGFR-Tyr1068 phosphorylation in NCI-H1975 cells was found to be potently inhibited by AC0010, as demonstrated by immunoblotting analysis. The selectivity ratio between NCI-H1975 and A431 cells is 65-fold. Apart from impeding the phosphorylation of EGFR-Tyr1068, AC0010 also prevented the phosphorylation of Akt and ERK1/2, two crucial kinases linked to the growth and endurance of cancer cells, in NCI-H1975 and HCC827 cells. An additional method of evaluating AC0010's selectivity was to measure its activity against a panel of 349 kinases. 33 of 349 distinct kinase tests (9.5%) showed that AC0010 inhibited more than 80% at a concentration of 1 μM. JAK3, BTK, and five members of the TEC family are among the kinase targets that exhibit more than 80% inhibition. The kinase inhibitory potency is, however, substantially lower at the cellular level than it is in the enzymatic assay. The cellular assays for BTK and JAK3 showed significantly less inhibition, with IC50 values of 59 nM and 360 nM, respectively. AC0010 (1 μM) inhibits 5 out of 55 targets, including Adenosine A3, L-type calcium (Cav1.2) channel, dopamine transporter, 5-HT2A, and 5-HT2B, with over 50% inhibition of radioligand binding when tested against a selected panel of 55 important molecular targets, including receptors, ion channels, and transporters. However, no inhibition was found for more than five targets in cell-based functional assays, suggesting that at pharmacologically relevant concentrations, the risk of off-target binding of AC0010 is negligible[1].

ln Vivo

For more than 143 days, and without causing weight loss, EGFR-positive tumors with T790M mutations were completely remitted when oral administration of 500 mg/kg of AC0010 per day was administered in a xenografte model. The total body clearance and volume of distribution of AC0010 were estimated to be 5.91 L/h/kg and 14.76 L/kg, respectively, for PK analysis after 10 mg/kg of the drug was administered intravenously to NCI-H1975 xenograft models. AC0010 has a rapid distribution into tissues, including tumor tissues, as evidenced by its elimination half-life (t1/2) of 1.73 hours. After being administered orally for one day or eight consecutive days at doses of 12.5 mg/kg, 50 mg/kg, and 200 mg/kg of AC0010, the drug was absorbed with a Tmax of one to two hours and a bioavailability of 15.9–41.4%. In animal models, AC0010 and its metabolites do not cause any off-target effects or skin lesions[1]. Patients with NSCLC who have EGFR T790m(+) respond well to avitinib. It has a low concentration in the cerebrospinal fluid and a weak BBB penetration. Nonetheless, it demonstrated a strong control of brain metastases (BM)[2].

Enzyme Assay

Reaction Biology Corp., a service provider, carried out the kinase activity assay (Malvern, PA, USA). AC0010 was utilized at a concentration of either 1 µM or 10 µM for the single dose screening assay. A 10-concentration gradient from 5.1x10^-11-1.0x10^-6 mol/L was set for the tested compounds in order to determine their IC50 values. In order to assess the assay quality for one-dose kinase activity assays and IC50 value calculations, staurosporine was used as a control compound.

Cell Assay

The cell viability reagent WST-1 was used to measure the proliferation of cells. After being optimally densely seeded onto 96-well plates, the cells underwent a 24-hour incubation period and a 72-hour compound treatment period. Next, cells were cultured with WST-1 reagent for two to three hours in order to test the viability of the cells.

Animal Protocol

Nu/Nu nude mice
12.5 mg/kg, 50 mg/kg and 500 mg/kg
oral

References

[1]. Mol Cancer Ther . 2016 Nov;15(11):2586-2597.

[2]. Journal of Clinical Oncology. 2017, 35 (15 suppl):e20613.

These protocols are for reference only. InvivoChem does not independently validate these methods.

Physicochemical Properties

Molecular Formula

C26H26FN7O2

Molecular Weight

487.53

Exact Mass

487.21

Elemental Analysis

C, 64.05; H, 5.38; F, 3.90; N, 20.11; O, 6.56

CAS #

1557267-42-1

Related CAS #

Avitinib maleate;1557268-88-8

Appearance

Solid powder

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

InChi Key

UOFYSRZSLXWIQB-UHFFFAOYSA-N

InChi Code

InChI=1S/C26H26FN7O2/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/h3-10,15-16H,1,11-14H2,2H3,(H,29,35)(H2,28,30,31,32)

Chemical Name

N-[3-[[2-[3-fluoro-4-(4-methylpiperazin-1-yl)anilino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]phenyl]prop-2-enamide

Synonyms

AC0010; AC-0010MA; AC-0010; AC 0010MA; AC 0010; AC0010MA; Abivertinib

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 Data

Solubility (In Vitro)

DMSO: ~97 mg/mL (~199 mM)

Water: <1mg/mL

Ethanol: ~97 mg/mL (~199 mM)

Solubility (In Vivo)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

Injection Formulations
(e.g. IP/IV/IM/SC)

Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

Oral Formulations

Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

(Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.0512 mL	10.2558 mL	20.5116 mL
	5 mM	0.4102 mL	2.0512 mL	4.1023 mL
	10 mM	0.2051 mL	1.0256 mL	2.0512 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.

Calculator

Mass

Concentration

Volume

Molecular Weight*

Calculate Reset

Molarity Calculator allows you to calculate the mass, volume, and/or concentration required for a solution, as detailed below:

Calculate the Mass of a compound required to prepare a solution of known volume and concentration
Calculate the Volume of solution required to dissolve a compound of known mass to a desired concentration
Calculate the Concentration of a solution resulting from a known mass of compound in a specific volume

See Example

An example of molarity calculation using the molarity calculator is shown below:
What is the mass of compound required to make a 10 mM stock solution in 5 ml of DMSO given that the molecular weight of the compound is 350.26 g/mol?

Enter 350.26 in the Molecular Weight (MW) box
Enter 10 in the Concentration box and choose the correct unit (mM)
Enter 5 in the Volume box and choose the correct unit (mL)
Click the “Calculate” button
The answer of 17.513 mg appears in the Mass box. In a similar way, you may calculate the volume and concentration.

Concentration (Start)

Volume (Start)

Concentration (End)

Volume (End)

Calculate Reset

Dilution Calculator allows you to calculate how to dilute a stock solution of known concentrations. For example, you may Enter C1, C2 & V2 to calculate V1, as detailed below:

What volume of a given 10 mM stock solution is required to make 25 ml of a 25 μM solution?
Using the equation C1V1 = C2V2, where C1=10 mM, C2=25 μM, V2=25 ml and V1 is the unknown:

Enter 10 into the Concentration (Start) box and choose the correct unit (mM)
Enter 25 into the Concentration (End) box and select the correct unit (mM)
Enter 25 into the Volume (End) box and choose the correct unit (mL)
Click the “Calculate” button
The answer of 62.5 μL (0.1 ml) appears in the Volume (Start) box

Molecular formula

Total molecular weight

g/mol

Calculate Reset

Molecular Weight Calculator allows you to calculate the molar mass and elemental composition of a compound, as detailed below:

Note: Chemical formula is case sensitive: C12H18N3O4 c12h18n3o4
Instructions to calculate molar mass (molecular weight) of a chemical compound:

To calculate molar mass of a chemical compound, please enter the chemical/molecular formula and click the “Calculate’ button.

Definitions of molecular mass, molecular weight, molar mass and molar weight:

Molecular mass (or molecular weight) is the mass of one molecule of a substance and is expressed in the unified atomic mass units (u). (1 u is equal to 1/12 the mass of one atom of carbon-12)
Molar mass (molar weight) is the mass of one mole of a substance and is expressed in g/mol.

Volume (to add to vial)

Mass (in vial)

Desired Reconstitution Concentration

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Reconstitution Calculator allows you to calculate the volume of solvent required to reconstitute your vial.

Enter the mass of the reagent and the desired reconstitution concentration as well as the correct units
Click the “Calculate” button
The answer appears in the Volume (to add to vial) box

In vivo Formulation Calculator (Clear solution)

Step 1: Enter information below (Recommended: An additional animal to make allowance for loss during the experiment)

Dosage mg/kg

Average weight of animals g

Dosing volume per animal μL

Number of animals

Step 2: Enter in vivo formulation (This is only a calculator, not the exact formulation for a specific product. Please contact us first if there is no in vivo formulation in the solubility section.)

% DMSO

% Tween 80

% ddH₂O

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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.

Note： (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.

Clinical Trial Information

NCT Number	Recruitment	interventions	Conditions	Sponsor/Collaborators	Start Date	Phases
NCT03856697	Not yet recruiting	Drug: Placebo Gefitinib Tablets Drug: Gefitinib Tablets	Advanced Non-small Cell Lung Cancer	Hangzhou ACEA Pharmaceutical Research Co., Ltd.	March 2019	Phase 3
NCT03574402	Recruiting	Drug: Avitinib Maleate Drug: Afatinib	Carcinoma, Non-Small-Cell Lung	Guangdong Association of Clinical Trials	July 9, 2018	Phase 2
NCT04440007	Completed	Drug: Abivertinib Other: Standard of Care	Covid-19	Sorrento Therapeutics, Inc.	October 9, 2020	Phase 2
NCT04528667	Completed	Drug: STI-5656 Drug: Placebo	Covid19	Sorrento Therapeutics, Inc.	January 6, 2021	Phase 2
NCT03053219	Completed	Drug: AC0010	Carcinoma，Non-Small-Cell Lung	Hangzhou ACEA Pharmaceutical Research Co., Ltd.	November 2016	Phase 1

Biological Data

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.