PHA-665752

製品コードS1070 バッチS107007

印刷

化学情報

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

C32H34Cl2N4O4S
分子量 641.61 CAS No. 477575-56-7
Solubility (25°C)* 体外 DMSO 100 mg/mL (155.85 mM)
Water Insoluble
Ethanol Insoluble
* <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.

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生物活性

製品説明 PHA-665752 is a potent, selective and ATP-competitive c-Met inhibitor with IC50 of 9 nM in cell-free assays, >50-fold selectivity for c-Met than RTKs or STKs.
in vitro PHA-665752 significantly inhibits c-Met kinase activity with Ki of 4 nM, and exhibits >50-fold selectivity for c-Met compared with various tyrosine and serine-threonine kinases. PHA-665752 potently inhibits the HGF-stimulated c-Met autophosphorylation with IC50 of 25-50 nM. PHA-665752 also significantly blocks HGF- and c-Met-dependent functions such as cell motility and cell proliferation with IC50 of 40-50 nM and 18-42 nM, respectively. In addition, PHA-665752 potently inhibits HGF-stimulated or constitutive phosphorylation of mediators of downstream of c-Met such as Gab-1, ERK, Akt, STAT3, PLC-γ, and FAK in multiple tumor cell lines. [1] PHA-665752 inhibits cell growth in TPR-MET-transformed BaF3 cells with IC50 of <60 nM, and inhibits constitutive cell motility and migration by 92.5% at 0.2 μM. Inhibition of c-Met by PHA665752 (0.2 μM) also induces cell apoptosis of 33.1% and G1 cell cycle arrest with cells in G1 phase increasing from 42.4% to 77.0%. PHA665752 can cooperate with rapamycin to inhibit cell growth of TPR-MET-transformed BaF3 cells and non-small cell lung cancer H441 cells. [2]
in vivo Administration of PHA-665752 induces a dose-dependent tumor growth inhibition of S114 xenografts by 20 %, 39% and 68%, at dose of 7.5, 15, and 30 mg/kg/day, respectively. [1] PHA665752 treatment significantly reduces the tumor growth of NCI-H69, NCI-H441 and A549 in mouse xenografts by 99%, 75%, and 59%, respectively. PHA665752 also significantly inhibits angiogenesis by >85%, due to decreasing the production of vascular endothelial growth factor and increasing the production of the angiogenesis inhibitor thrombospondin-1. [3]

プロトコル(参考用のみ)

キナーゼアッセイ In vitro enzyme assay
The c-Met kinase domain GST-fusion protein is used for the c-Met assay. The IC50 value of PHA-665752 for the inhibition of c-Met is based on phosphorylation of kinase peptide substrates or poly-glu-tyr in the presence of ATP and divalent cation (MgCl2 or MnCl2 10-20 mM). The linear range (i.e., the time period over which the rate remains equivalent to the initial rate) is determined for c-Met, and the kinetic measurement and IC50 determination are performed within this range.
細胞アッセイ 細胞株 S114, GTL-16, NCI-H441, and BxPC-3
濃度 Dissolved in DMSO, final concentrations ~10 μM
反応時間 18, or 72 hours
実験の流れ For proliferation assays, cells are grown in medium with 0.1% FBS for 48 hours after which they are treated with various concentrations of PHA-665752 in HGF (50 ng/mL) in a medium containing 2% FBS. After 18 hours, cells are incubated with BrdUrd for 1 hour, fixed, and stained with anti-BrdUrd peroxidase-conjugated antibody, and plates are read at 630 nm. For apoptosis assays, cells are grown in medium with 2% FBS in presence and absence of HGF (50 ng/mL) and various concentrations of PHA-665752 for 72 hours. After 72 hours, a mixture containing ethidium bromide and acridine orange is added, and apoptotic cells (bright orange cells or cell fragments) are counted by fluorescence microscopy.
動物実験 動物モデル Female athymic mice (nu/nu) bearing S114 or GTL-16 tumor xenografts
投薬量 ~30 mg/kg/day
投与方法 Injection via bolus i.v.

カスタマーフィードバック

Data from [Data independently produced by Clin Cancer Res, 2014, 20, 4806-15]

Data from [Data independently produced by Cancer Res, 2014, 74, 253-62]

Data from [Data independently produced by Biochem Biophys Res Commun, 2014, 449(1), 49-54]

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：

MET receptor serves as a promising target in melanoma brain metastases [ Acta Neuropathol, 2024, 147(1):44] PubMed: 38386085
LncRNA CHROMR/miR-27b-3p/MET axis promotes the proliferation, invasion, and contributes to rituximab resistance in diffuse large B-cell lymphoma [ J Biol Chem, 2024, 300(3):105762] PubMed: 38367665
Single targeting of MET in EGFR-mutated and MET-amplified non-small cell lung cancer [ Br J Cancer, 2023, 128(12):2186-2196] PubMed: 37059804
Cancer-Associated Fibroblasts Promote Radioresistance of Breast Cancer Cells via the HGF/c-Met Signaling Pathway [ Int J Radiat Oncol Biol Phys, 2023, 116(3):640-654] PubMed: 36586496
MET Receptor Tyrosine Kinase Inhibition Reduces Interferon-Gamma (IFN-γ)-Stimulated PD-L1 Expression through the STAT3 Pathway in Melanoma Cells [ Cancers (Basel), 2023, 15(13)3408] PubMed: 37444518
MET Receptor Tyrosine Kinase Inhibition Reduces Interferon-Gamma (IFN-γ)-Stimulated PD-L1 Expression through the STAT3 Pathway in Melanoma Cells [ Cancers (Basel), 2023, 15(13)3408] PubMed: 37444518
Cabozantinib inhibits HBV-RNA transcription by decreasing STAT3 binding to the enhancer region of cccDNA [ Hepatol Commun, 2023, 10.1097/HC9.0000000000000313] PubMed: 37938099
Dual-targeting therapy against HER3/MET in human colorectal cancers [ Cancer Med, 2023, 10.1002/cam4.5673] PubMed: 36751113
Integrative analysis of drug response and clinical outcome in acute myeloid leukemia [ Cancer Cell, 2022, S1535-6108(22)00312-9] PubMed: 35868306
Crizotinib attenuates cancer metastasis by inhibiting TGFβ signaling in non-small cell lung cancer cells [ Exp Mol Med, 2022, 54(8):1225-1235] PubMed: 35999455

長期の保管のために-20°Cの下で製品を保ってください。

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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