Neratinib

製品コードS2150 バッチS215006

印刷

化学情報

Chemical Structure Synonyms HKI-272 Storage
(From the date of receipt)		 3 years -20°C powder
1 years -80°C in solvent
化学式

C30H29ClN6O3
分子量 557.04 CAS No. 698387-09-6
Solubility (25°C)* 体外 DMSO (warmed with 50ºC water bath) 7 mg/mL (12.56 mM)
Water Insoluble
Ethanol Insoluble
体内 （毎回新しく調製した物を用意してください）
Homogeneous suspension
CMC-NA
≥5mg/ml Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

溶剤液（一定の濃度）を調合する

生物活性

製品説明 Neratinib is a highly selective HER2 and EGFR inhibitor with IC50 of 59 nM and 92 nM in cell-free assays; weakly inhibits KDR and Src, no significant inhibition to Akt, CDK1/2/4, IKK-2, MK-2, PDK1, c-Raf and c-Met. Phase 3.
in vitro Neratinib weakly inhibits tyrosine kinases KDR and Src with IC50 of 0.8 μM and 1.4 μM, respectively, being 14- and 24-fold less active compared with HER2. This compound displays no activity against other serine-threonine kinases such as Akt, cyclin D1/cdk4, cyclin E/cdk2, cyclin B1/cdk1, IKK-2, MK-2, PDK1, c-Raf, and Tpl-2, as well as the tyrosine kinase c-Met. It selectively inhibits the proliferation of 3T3 cells transfected with the HER2 (3T3/neu), as well as two other HER-2-overexpressing SK-Br-3 and BT474 cells with IC50 values of 2-3 nM, displaying >230-fold potency compared with non-transfected 3T3 cells as well as MDA-MB-435 and SW620 which are EGFR- and HER2-negative. This chemical also inhibits the proliferation of EGFR-dependent A431 cells with an IC50 of 81 nM. It reduces HER2 receptor autophosphorylation in BT474 cells with an IC50 of 5 nM, and EGF-dependent phosphorylation of EGFR in A431 cells with IC50 of 3 nM. Blocking of HER-2 by this compound results in inhibition of downstream MAPK and Akt pathways with IC50 of 2 nM, more potently than Trastuzumab. It inhibits the cyclin D1 expression and the phosphorylation of the Rb-susceptibility gene production in BT474 cells with IC50 of 9 nM, leading to G1-S arrest and ultimately decreased cell proliferation. [1]
in vivo Oral administration of Neratinib significantly inhibits the growth of 3T3/neu xenografts, with inhibition of 34%, 53%, 98%, and 98% at dose of 10, 20, 40, and 80 mg/kg/day, respectively. Consistent with the inhibition of HER-2 phosphorylation by 84% within 1 hour of administration at 40 mg/kg/day, this compound inhibits the growth of BT474 xenografts by 70-82%, 67%, and 93% at dose of 5, 10, and 40 mg/kg/day, respectively. It is also effective against SK-OV-3 xenografts with inhibition of 31% and 85% at 5 and 60 mg/kg/day, respectively. This chemical is less potent against EGFR-dependent A431 xenografts than HER-2-dependent tumors, with 32% and 44% inhibition at 5 and 20 mg/kg/day, respectively. It displays little activity against MCF-7 and MX-1 xenografts expressing low levels of HER-2 and EGFR, with only 28% inhibition at 80 mg/kg/day, suggesting that it has selective activity for cells expressing HER-2 or EGFR. [1]

プロトコル(参考用のみ)

キナーゼアッセイ Cell-free autophosphorylation assay using time-resolved fluorometry
Neratinib is prepared as 10 mg/mL stocks in DMSO and diluted in 25 mM HEPES (pH 7.5; 0.002 ng/mL-20 μg/mL). Purified recombinant COOH-terminal fragments of HER2 (amino acids 676-1255) or epidermal growth factor receptor (EGFR) (amino acids 645-1186) [diluted in 100 mM HEPES (pH 7.5) and 50% glycerol] is incubated with increasing concentrations of this compound in 4 mM HEPES (pH 7.5), 0.4 mM MnCl2, 20 μM sodium vanadate, and 0.2 mM DTT for 15 minutes at room temperature in 96-well ELISA plates. The kinase reaction is initiated by the addition of 40 μM ATP and 20 mM MgCl2 and allowed to proceed for 1 hour at room temperature. Plates are washed, and phosphorylation is detected using Europium-labeled anti-phospho-tyrosine antibodies (15 ng/well). After washing and enhancement steps, signal is detected using a Victor2 fluorescence reader (excitation wavelength 340 nm, emission wavelength 615 nm). The concentration of this chemical that inhibits receptor phosphorylation by 50% (IC50) is calculated from inhibition curves.
細胞アッセイ 細胞株 3T3, 3T3/neu, A431, BT474, SK-Br-3, MDA-MB-435, and SW480
濃度 Dissolved in DMSO, final concentrations 0.5 ng/mL-5 μg/mL
反応時間 2 or 6 days
実験の流れ Cells are exposed to various concentrations of Neratinib for 2, or 6 days. Cell proliferation is determined using sulforhodamine B, a protein binding dye. Briefly, cells are fixed with 10% trichloroacetic acid and washed extensively with water. Cells are then stained with 0.1% sulforhodamine B and washed in 5% acetic acid. Protein-associated dye is solubilized in 10 mM Tris, and absorbance is measured at 450 nM. The concentration of this compound that inhibits cell proliferation by 50% (IC50) is determined from inhibition curves.
動物実験 動物モデル Female athymic (nude) mice implanted s.c. with 3T3/neu, BT474, MCF-7, or SK-OV-3 cells
投薬量 ~80 mg/kg/day
投与方法 Gavage

参考

  • https://pubmed.ncbi.nlm.nih.gov/15173008/

カスタマーフィードバック

Data from [Cancer Discov, 2013, 3, 224-37]

Data from [Cancer Discov, 2012, 2, 458-471]

Data from [Cancer Discov, 2012, 2, 458-471]

Selleckの高級品が、幾つかの出版された研究調査結果（以下を含む）で使われた：

Small molecule kinase inhibitor altiratinib inhibits brain cyst forming bradyzoites of Toxoplasma gondii [ J Microbiol, 2025, 63(2):e2409001] PubMed: 40044130
Hotspot mutations in HER2 interfaces destabilize structure, causing breast cancer treatment failure [ Res Sq, 2025, rs.3.rs-5931887] PubMed: 40166021
Proteogenomic analysis dissects early-onset breast cancer patients with prognostic relevance [ Exp Mol Med, 2024, 56(11):2382-2394] PubMed: 39482530
Peptidylarginine deiminase 3 modulates response to neratinib in HER2 positive breast cancer [ Oncogenesis, 2024, 13(1):30] PubMed: 39097594
Patient-derived rhabdomyosarcoma cells recapitulate the genetic and transcriptomic landscapes of primary tumors [ iScience, 2024, 27(10):110862] PubMed: 39319271
Synergistic Effects of Neratinib in Combination With Palbociclib or Miransertib in Brain Cancer Cells [ World J Oncol, 2024, 15(3):492-505] PubMed: 38751701
The Combination of Afatinib With Dasatinib or Miransertib Results in Synergistic Growth Inhibition of Stomach Cancer Cells [ World J Oncol, 2024, 15(2):192-208] PubMed: 38545471
HER4 and EGFR activate cell signaling in NRG1 fusion-driven cancers: implications for HER2/HER3-specific vs. pan-HER targeting strategies [ J Thorac Oncol, 2023, S1556-0864(23)00802-X] PubMed: 37678511
Irreversible HER2 inhibitors overcome resistance to the RSL3 ferroptosis inducer in non-HER2 amplified luminal breast cancer [ Cell Death Dis, 2023, 14(8):532] PubMed: 37596261
Irreversible HER2 inhibitors overcome resistance to the RSL3 ferroptosis inducer in non-HER2 amplified luminal breast cancer [ Cell Death Dis, 2023, 14(8):532] PubMed: 37596261

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人間や獣医の診断であるか治療的な使用のためにでない。

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