Avitinib (AC0010)

製品コードS8741

Avitinib (AC0010)化学構造

分子量(MW):487.53

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.

サイズ 価格(税別)  
JPY 13968.68
JPY 41760.72
JPY 99360.36

製品安全説明書

EGFR阻害剤の選択性比較

生物活性

製品説明 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.
ターゲット
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
体外試験

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].

体内試験

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].

お薦めの試験操作(参考用のみ)

キナーゼ試験:

[1]

+ 展開

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.
細胞試験:

[1]

+ 展開
  • 細胞株: NCI-H1975, HCC827, A431 and NIH/3T3_TC32T8 cells
  • 濃度: --
  • 反応時間: 72 h
  • 実験の流れ:

    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.


    (参考用のみ)
動物試験:

[1]

+ 展開
  • 動物モデル: Nu/Nu nude mice
  • 製剤: 0.5% methylcellulose
  • 投薬量: 12.5 mg/kg, 50 mg/kg and 500 mg/kg
  • 投与方法: oral
    (参考用のみ)

溶解度 (25°C)

体外 DMSO 97 mg/mL (198.96 mM)
Ethanol 97 mg/mL (198.96 mM)
Water Insoluble

* 溶解度測定はSelleck技術部門によって行われており、その他文献に示されている溶解度と差異がある可能性がありますが、同一ロットの生産工程で起きる正常な現象ですからご安心ください。

化学情報

分子量 487.53
化学式

C26H26FN7O2

CAS No. 1557267-42-1
保管
in solvent
別名 N/A

便利ツール

モル濃度計算器

モル濃度計算器

求めたい質量、体積または濃度を計算してください。

質量 (g) = 濃度 (mol/L) x 体積 (L) x 分子量 (g/mol)

モル濃度計算器方程式

  • 質量
    濃度
    体積
    分子量

*貯蔵液を準備するとき、常に、オンであるとわかる製品のバッチに特有の分子量を使って、を通してラベルとMSDS/COA(製品ページで利用可能な)。

希釈計算器

希釈計算器

貯蔵液を準備するために必要な希釈率を計算してください。Selleck希釈計算器は、以下の方程式に基づきます:

開始濃度 x 開始体積 = 最終濃度 x 最終体積

希釈の計算式

この方程式は、一般に略語を使われます:C1V1 = C2V2 ( 入力 出力 )

  • C1
    V1
    C2
    V2

常に貯蔵液を準備するとき、小びんラベルとMSDS/COA(オンラインで利用できる)で見つかる製品のバッチに特有の分子量を使ってください。

連続希釈計算器方程式

  • 連続希釈剤

  • 計算結果

  • C1=C0/X C1: LOG(C1):
    C2=C1/X C2: LOG(C2):
    C3=C2/X C3: LOG(C3):
    C4=C3/X C4: LOG(C4):
    C5=C4/X C5: LOG(C5):
    C6=C5/X C6: LOG(C6):
    C7=C6/X C7: LOG(C7):
    C8=C7/X C8: LOG(C8):
分子量計算器

分子量计算器

そのモル質量と元素組成を計算するために、合成物の化学式を入力してください:

総分子量:g/mol

チップス: 化学式は大文字と小文字の区別ができます。C10H16N2O2 c10h16n2o2

モル濃度計算器

質量 濃度 体積 分子量

臨床試験

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT03058094 Not yet recruiting NSCLC Hangzhou ACEA Pharmaceutical Research Co.Ltd.|Cancer Institute and Hospital Chinese Academy of Medical Sciences December 2018 Phase 3
NCT03574402 Not yet recruiting Carcinoma Non-Small-Cell Lung Guangdong Association of Clinical Trials July 1 2018 Phase 2
NCT03300115 Recruiting Metastatic Non-small Cell Lung Cancer Hangzhou ACEA Pharmaceutical Research Co.Ltd.|Guangdong General Hospital|Acea Bio (Hangzhou) Co. Ltd. May 18 2017 Phase 2
NCT03060850 Recruiting B-cell Lymphoma Hangzhou ACEA Pharmaceutical Research Co.Ltd. March 17 2017 Phase 1
NCT03053219 Recruiting Carcinoma,Non-Small-Cell Lung Hangzhou ACEA Pharmaceutical Research Co.Ltd. November 2016 Phase 1
NCT03001609 Completed Carcinoma Non-Small-Cell Lung Hangzhou ACEA Pharmaceutical Research Co.Ltd. November 2016 Phase 1

技術サポート

ストックの作り方、阻害剤の保管方法、細胞実験や動物実験の際に注意すべき点など、製品を取扱う時に問い合わせが多かった質問に対しては取扱説明書でお答えしています。

Handling Instructions

他に質問がある場合は、お気軽にお問い合わせください。

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