PHA-665752

카탈로그 번호S1070 배치:S107006

인쇄

기술 자료

화학식

C32H34Cl2N4O4S
분자량 641.61 CAS 번호 477575-56-7
용해도 (25°C)* 시험관 내(In vitro) DMSO 100 mg/mL (155.85 mM)
Water Insoluble
Ethanol Insoluble
생체 내(In Vivo) (개별적으로 순서대로 용매를 제품에 첨가하십시오.)
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.
Clear solution
5% DMSO 95% corn oil

Selleck 연구소에서 검증했습니다. 이 제형에 대한 조정이 필요한 경우 맞춤형 테스트를 위해 당사 영업팀에 문의하십시오.

 0.460mg/ml (0.72mM) Taking the 1 mL working solution as an example, add 50 μL of clarified DMSO stock solution of 9.2 mg/ml to 950 μL of corn oil, mix evenly to clarify it, and prepare the working solution for immediate use!
* <1 mg/ml은 약간 용해되거나 불용해됨을 의미합니다.
* Selleck은 모든 화합물의 용해도를 자체적으로 테스트하며, 실제 용해도는 게시된 값과 약간 다를 수 있습니다. 이는 정상적인 현상이며, 약간의 배치 간 변동으로 인해 발생합니다.
* 실온 배송 (안정성 테스트 결과 이 제품은 냉각 조치 없이 배송될 수 있음을 보여줍니다.)

원액 준비

생물학적 활성

설명 PHA-665752는 c-Met에 대해 강력하고 선택적이며 ATP 경쟁적인 억제제로, 무세포 분석에서 9 nM의 IC50 값을 가지며 RTK나 STK보다 c-Met에 대해 50배 이상의 선택성을 보입니다.
표적
c-Met
(Cell-free assay)		 RON
(Cell-free assay)		 Flk1
(Cell-free assay)
9 nM 68 nM 200 nM
시험관 내(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.
생체 내(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.

프로토콜 (참조)

키나아제 분석:[1]
  • In vitro 효소 분석

    c-Met 키나아제 도메인 GST-융합 단백질은 c-Met 분석에 사용됩니다. c-Met 억제에 대한 PHA-665752의 IC50 값은 ATP 및 2가 양이온(MgCl2 또는 MnCl2 10-20 mM) 존재 하에서 키나아제 펩타이드 기질 또는 poly-glu-tyr의 인산화를 기반으로 합니다. c-Met에 대한 선형 범위(즉, 속도가 초기 속도와 동일하게 유지되는 기간)가 결정되며, 운동학적 측정 및 IC50 결정은 이 범위 내에서 수행됩니다.
세포 분석:[1]
  • 세포주

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

  • 농도

    Dissolved in DMSO, final concentrations ~10 μM

  • 배양 시간

    18, or 72 hours

  • 방법

    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.
동물 연구:[1]
  • 동물 모델

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

  • 용량

    ~30 mg/kg/day

  • 투여

    Injection via bolus i.v.

참조

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

고객 제품 검증

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.

데이터 출처 [ 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.

데이터 출처 [ 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.

데이터 출처 [ 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.

데이터 출처 [ Biochem Biophys Res Commun , 2014 , 449, 49-54 ]

Selleck's PHA-665752 인용됨 100 출판물

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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