Avitinib (AC0010)

Catalog No.S8741

For research use only.

Avitinib (AC0010) is a pyrrolopyrimidine-based irreversible EGFR inhibitor that is mutation-selective with IC50 value of 0.18 nM against EGFR L858R/T790M double mutations, nearly 43-fold greater potency over wild-type EGFR (IC50 value, 7.68 nM). It has comparable anti-tumor activity and tolerated toxicity.

Avitinib (AC0010) Chemical Structure

CAS No. 1557267-42-1

Purity & Quality Control

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Biological Activity

Description Avitinib (AC0010) is a pyrrolopyrimidine-based irreversible EGFR inhibitor that is mutation-selective with IC50 value of 0.18 nM against EGFR L858R/T790M double mutations, nearly 43-fold greater potency over wild-type EGFR (IC50 value, 7.68 nM). It has comparable anti-tumor activity and tolerated toxicity.
Targets
JAK3 [1]
(Cell-free assay)
EGFR L858R/T790M [1]
(Cell-free assay)
BTK [1]
(Cell-free assay)
0.09 nM 0.18 nM 0.4 nM
In vitro

AC0010 selectively inhibits EGFR active and T790M mutations with up to 298-fold increase in potency compared to wild-type EGFR. AC0010 selectively inhibited mutant EGFR phosphorylation with IC50 values of 7.3 nM and 2.8 nM in NCI-H1975 and NIH/3T3_TC32T8 cells, about 115- and 298-fold more sensitive than that of the inhibition of wild type EGFR in A431. Immunoblotting analysis confirmed that AC0010 potently inhibited EGFR-Tyr1068 phosphorylation in NCI-H1975 cells, and the selectivity ratio is at 65-fold for NCI-H1975 cells versus A431 cells. In addition to inhibition of EGFR-Tyr1068 phosphorylation, AC0010 inhibited phosphorylation of the downstream targets Akt and ERK1/2, two important kinases involved in cancer cell proliferation and survival, in NCI-H1975 and HCC827 cells. The selectivity of AC0010 was also assessed by testing its activity against a panel of 349 kinases. At a concentration of 1 μM, AC0010 exhibited greater than 80% inhibition in 33 out of 349 unique kinase assays (9.5%). Kinase targets with greater than 80% inhibition include JAK3, BTK and 5 TEC family members. However, at the cellular level, the kinase inhibitory potency is much less than with the enzymatic assay. Much weaker inhibition was seen in BTK and JAK3 cellular assays with IC50 values of 59 nM and 360 nM. When tested against a selected panel of 55 key molecular targets including receptors, ion channels and transporters, AC0010 (1 μM) inhibits 5 out of 55 targets over 50% inhibition of radioligand binding, including Adenosine A3, L-type calcium (Cav1.2) channel, dopamine transporter, 5-HT2A and 5-HT2B. However, in cell-based functional assays, no inhibition was detected for above 5 targets, implying that the risk of off-target binding of AC0010 is minimal at pharmacologically relevant concentrations[1].

In vivo

In a xenografte model, oral administration of AC0010 at daily dose of 500 mg/kg resulted in complete remission of tumors with EGFR active and T790M mutations for over 143 days with no weight loss. For PK analysis, following intravenous administration of 10 mg/kg of AC0010 in NCI-H1975 xenograft models, total body clearance and volume of distribution of AC0010 were estimated to be 5.91 L/h/kg and 14.76 L/kg, respectively. The elimination half-life (t1/2) of AC0010 was about 1.73 hour, indicating AC0010 is rapidly distributed into tissues including tumor tissues. Following oral administration of 12.5 mg/kg, 50 mg/kg and 200 mg/kg of AC0010 for 1 day or 8 consecutive days, AC0010 was absorbed with the Tmax of 1 to 2 hours, and bioavailability of 15.9-41.4%. AC0010 and its metabolites show no off-target effects and no skin lesion in animal models[1]. Avitinib is well tolerated and efficacious in EGFR T790m(+) NSCLC patients. Its concentration in cerebrospinal fluid is low, and the penetrability of BBB is weak. But it still showed a good control of brain metastases (BM)[2].

Protocol (from reference)

Kinase Assay:

[1]

  • In vitro kinase activity assay:

    Kinase activity assay was performed by service provider, Reaction Biology Corp (Malvern, PA, USA). For the single dose screening assay, AC0010 concentration at either 1 µM or 10 µM was used. For IC50 value determinations, a 10-concentration gradient from 5.1x10-11-1.0x10-6 mol/L was set for the tested compounds. Staurosporine served as a control compound to monitor assay quality for IC50 value determinations and one-dose kinase activity assay.

Cell Research:

[1]

  • Cell lines: NCI-H1975, HCC827, A431 and NIH/3T3_TC32T8 cells
  • Concentrations: --
  • Incubation Time: 72 h
  • Method:

    Cell proliferation was assayed by a cell viability reagent, WST-1. Cells were seeded at optimal density onto 96-well plates and incubated for 24 hours, followed by compound treatment for 72 hours. Cell viability was then assayed by incubating cells with WST-1 reagent for 2~3 hrs.

Animal Research:

[1]

  • Animal Models: Nu/Nu nude mice
  • Dosages: 12.5 mg/kg, 50 mg/kg and 500 mg/kg
  • Administration: oral

Solubility (25°C)

In vitro

Chemical Information

Molecular Weight 487.53
Formula

C26H26FN7O2

CAS No. 1557267-42-1
Storage 3 years -20°C powder
2 years -80°C in solvent
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

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Clinical Trial Information

NCT Number Recruitment Interventions Conditions Sponsor/Collaborators Start Date Phases
NCT03060850 Unknown status Drug: AC0010MA B-cell Lymphoma Hangzhou ACEA Pharmaceutical Research Co. Ltd. March 17 2017 Phase 1
NCT03001609 Completed Drug: AC0010 Carcinoma Non-Small-Cell Lung Hangzhou ACEA Pharmaceutical Research Co. Ltd. November 2016 Phase 1
NCT02448251 Terminated Drug: AC0010MA Non Small Cell Lung Cancer ACEA Therapeutics Inc. May 2015 Phase 1
NCT02274337 Unknown status Drug: AC0010 Non-Small Cell Lung Cancer Sun Yat-sen University|Acea Bio (Hangzhou) Co. Ltd.|Hangzhou ACEA Pharmaceutical Research Co. Ltd. September 2014 Phase 1|Phase 2

(data from https://clinicaltrials.gov, updated on 2022-08-01)

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

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