PHA-665752

Katalognr.S1070 Batch:S107007

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Tekniska data

Formel

C32H34Cl2N4O4S
Molekylvikt 641.61 CAS-nr. 477575-56-7
Löslighet (25°C)* In vitro DMSO 100 mg/mL (155.85 mM)
Water Insoluble
Ethanol Insoluble
In Vivo (Tillsätt lösningsmedel till produkten individuellt och i ordning.)
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 betyder svårlösligt eller olösligt.
* Vänligen notera att Selleck testar lösligheten för alla förbindelser internt, och den faktiska lösligheten kan skilja sig något från publicerade värden. Detta är normalt och beror på små variationer mellan olika partier.
* Rumstempererad frakt (Stabilitetstester visar att denna produkt kan fraktas utan några kylåtgärder.)

Beredning av stamlösningar

Biologisk aktivitet

Beskrivning PHA-665752 är en potent, selektiv och ATP-kompetitiv c-Met-hämmare med IC50 på 9 nM i cellfria analyser, >50 gånger selektivitet för c-Met än RTKs eller STKs.
Mål
c-Met
(Cell-free assay)		 RON
(Cell-free assay)		 Flk1
(Cell-free assay)
9 nM 68 nM 200 nM
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. This compound potently inhibits the HGF-stimulated c-Met autophosphorylation with IC50 of 25-50 nM. It 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, this chemical 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. It 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 this compound (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%. It can cooperate with rapamycin to inhibit cell growth of TPR-MET-transformed BaF3 cells and non-small cell lung cancer H441 cells.
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. This compound treatment significantly reduces the tumor growth of NCI-H69, NCI-H441 and A549 in mouse xenografts by 99%, 75%, and 59%, respectively. It 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.

Protokoll (från referens)

Kinasanalys:[1]
  • In vitro enzymanalys

    c-Met-kinasdomänens GST-fusionsprotein används för c-Met-analysen. IC50-värdet för PHA-665752 för hämning av c-Met baseras på fosforylering av kinaspeptidsubstrat eller poly-glu-tyr i närvaro av ATP och divalent katjon (MgCl2 eller MnCl2 10-20 mM). Det linjära området (d.v.s. tidsperioden under vilken hastigheten förblir ekvivalent med den initiala hastigheten) bestäms för c-Met, och den kinetiska mätningen och IC50-bestämningen utförs inom detta område.
Cellanalys:[1]
  • Cellinjer

    S114, GTL-16, NCI-H441, and BxPC-3

  • Koncentrationer

    Dissolved in DMSO, final concentrations ~10 μM

  • Inkubationstid

    18, or 72 hours

  • Metod

    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 this compound 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.
Djurstudie:[1]
  • Djurmodeller

    Female athymic mice (nu/nu) bearing S114 or GTL-16 tumor xenografts

  • Doseringar

    ~30 mg/kg/day

  • Administrering

    Injection via bolus i.v.

Referenser

  • https://pubmed.ncbi.nlm.nih.gov/14612533/
  • https://pubmed.ncbi.nlm.nih.gov/15788682/
  • https://pubmed.ncbi.nlm.nih.gov/17440059/

Kundvalidering av produkt

A, representative Western blot analyses of samples obtained from NSCLC cells exposed to 1 umol/L erlotinib or PHA-665,752 for 6 hours. Levels of total and phosphorylated forms of EGFR, MET, and HER3. B, representative Western blot analyses of samples obtained as described in A showing the levels of EGFR downstream signaling mediators. Protein samples obtained from untreated and treated cells were separated by SDS-PAGE and immunoblotted with each antibody. Tubulin served to ensure equal loading.

Data från [ Clin Cancer Res , 2014 , 20, 4806-15 ]

A, SCID mice bearing established HCC827/GR tumor cell xenografts were treated with each drug. The length and width of the tumors were measured at the days indicated and tumor volumes were calculated. The bars represent mean tumor volume ?SD. B, immunohistochemical staining for Ki-67 and TUNEL, as described in Materials and Methods. Quantitative data for proliferation and apoptotic indices are shown as Ki-67+ cells (left) and TUNEL+ cells (right). *, P < 0.01 and **, P < 0.001 for the combination of gefitinib plus NPS-1034 or gefitinib plus PHA-665752 versus either the control or drug alone.

Data från [ Cancer Res , 2014 , 74, 253-62 ]

PHA-665752 increases the radiosensitivity and reverses the radioresistance induced by HGF in NPC cells. Radiosensitization induced by PHA-665752 is accompanied by the persistence of the c-H2AX foci. Representative immunofluorescence micrographs of the c-H2AX foci formation in PHA-665752 (1 uM), HGF (20 ng/ml), IR and their combination groups. The micrographs were taken at x 400 magnification.

Data från [ Biochem Biophys Res Commun , 2014 , 449(1), 49-54 ]

Radiosensitization induced by PHA-665752 is accompanied by the persistence of the γ-H2AX foci. (Top) Representative immunofluorescence micrographs of the γ-H2AX foci formation in PHA-665752 (1 uM), HGF (20 ng/ml), IR and their combination groups. The micrographs were taken at x400 magnification. (Bottom) The median number of the γ-H2AX foci per cell. The bars indicate the SD. ∗P < 0.01 compared with the IR alone group.

Data från [ Biochem Biophys Res Commun , 2014 , 449, 49-54 ]

Sellecks PHA-665752 Har citerats av 100 Publikationer

Inhibition of TFF3 synergizes with c-MET inhibitors to decrease the CSC-like phenotype and metastatic burden in ER+HER2+ mammary carcinoma [ Cell Death Dis, 2025, 16(1):76] PubMed: 39920140
Macrophage Subpopulation Promotes Skeletal Muscle Regeneration Through HGF/MET Signaling-Mediated Skeletal Muscle Stem Cell Proliferation [ Aging Cell, 2025, e70042.] PubMed: 40132988
Overcoming MET-targeted drug resistance in MET-amplified lung cancer by aurora kinase B inhibition [ Biochim Biophys Acta Mol Cell Res, 2025, 1872(7):120001] PubMed: 40499687
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
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

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