PHA-665752 is an ATP-competitive and selective c-Met inhibitor with Ki value of 4nM, exhibiting >50-fold selectivity for c-Met compared with a panel of diverse tyrosine and serine-threonine kinases. PHA-665752 dose-dependently inhibited HGF-induced c-Met phosphorylation in A549 cells at concentration ranging in 0.025-0.2μM and suppressed HGF-induced migration in NCI-H441 cells at concentration of 0.1μM. Treatment with 0.1μM PHA-665752 for 3 hours could potently inhibit constitutive signaling through ERK, Akt, FAK, PLC-γ and STAT pathways in GTL-16 cells. Intravenous injection with PHA-665752 could dose-dependently reduce the tumor growth of athymic mice bearing S114 tumors at dose of 7.5, 15 and 30mg/kg, daily for 10 days, and significantly inhibit the tumor growth in the GTL-16 gastric tumor xenograft model, at dose of 25mg/kg, daily for 9 days.
PHA-665752 细胞实验
Cell Line
Concentration
Treated Time
Description
References
GTL-16
100 nM
4 h
To evaluate the inhibitory effect of PHA-665752 on MET phosphorylation
Clin Cancer Res. 2016 Jul 15;22(14):3683-94.
HT29
100 nM
4 h
To evaluate the inhibitory effect of PHA-665752 on MET phosphorylation
Clin Cancer Res. 2016 Jul 15;22(14):3683-94.
A549
100 nM
4 h
To evaluate the inhibitory effect of PHA-665752 on MET phosphorylation
Clin Cancer Res. 2016 Jul 15;22(14):3683-94.
SNU1076
1 μM
24 h
To study the effect of MET activation on cetuximab efficacy, results showed that PHA-665752 reversed MAPK pathway inhibition
Int J Cancer. 2019 Aug 1;145(3):748-762.
HSC4
1 μM
24 h
To study the effect of MET activation on cetuximab efficacy, results showed that PHA-665752 reversed MAPK pathway inhibition
Int J Cancer. 2019 Aug 1;145(3):748-762.
44As3 cells
100 nM or 300 nM
2 h
To evaluate the inhibitory effect of PHA-665752 on Met phosphorylation in 44As3 cells
Cancer Sci. 2014 May;105(5):528-36.
58As9 cells
100 nM or 300 nM
2 h
To evaluate the inhibitory effect of PHA-665752 on Met phosphorylation in 58As9 cells
Cancer Sci. 2014 May;105(5):528-36.
FG cells
0.1 μM
48 h
To investigate the effect of PHA-665752 on FOXM1 expression in FG cells, results showed that PHA-665752 inhibited the HGF/Met signaling pathway, thereby reducing FOXM1 expression.
Oncogene. 2016 Sep 8;35(36):4708-18.
PANC-1 cells
0.1 μM
48 h
To investigate the effect of PHA-665752 on the expression of FOXM1 downstream target genes in PANC-1 cells, results showed that PHA-665752 inhibited the HGF/Met signaling pathway, thereby reducing the expression of FOXM1 downstream target genes.
Oncogene. 2016 Sep 8;35(36):4708-18.
GTL16 cells
250 nM
PHA-665752 significantly impaired the viability and growth ability of GTL16 cells, but upon stimulation with EGF or HRG1-β1, cells were able to partially overcome the inhibitory effect of PHA-665752.
Mol Cancer. 2010 May 26;9:121.
SNU5
50 nM
PHA-665752 significantly impaired the viability and growth ability of these cells, but upon stimulation with EGF or HRG1-β1, cells were able to partially overcome the inhibitory effect of PHA-665752.
Mol Cancer. 2010 May 26;9:121.
MRC-5 cells
1 µM
24 h
Inhibition of HGF signaling to study the effect of PHA-665752 on fibronectin expression in MRC-5 cells. Results showed that PHA-665752 significantly inhibited the suppressive effects of OSM-MSC conditioned medium on fibronectin expression.
Stem Cells Transl Med. 2017 Mar;6(3):1006-1017.
MESO924
1 µM
72 h
PHA-665752 exhibited antiproliferative effects in MESO924 cells by inhibiting MET-dependent PI3K/AKT and RAF/MAPK signaling pathways
Br J Cancer. 2014 May 13;110(10):2479-88.
MESO257
1 µM
72 h
PHA-665752 exhibited antiproliferative effects in MESO257 cells by inhibiting MET-dependent PI3K/AKT and RAF/MAPK signaling pathways
Br J Cancer. 2014 May 13;110(10):2479-88.
MESO296
1 µM
72 h
PHA-665752 exhibited antiproliferative effects in MESO296 cells by inhibiting MET-dependent PI3K/AKT and RAF/MAPK signaling pathways
Br J Cancer. 2014 May 13;110(10):2479-88.
MESO428
1 µM
72 h
PHA-665752 exhibited antiproliferative effects in MESO428 cells by inhibiting MET-dependent PI3K/AKT and RAF/MAPK signaling pathways
Br J Cancer. 2014 May 13;110(10):2479-88.
PHA-665752 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
CAL33 cell line-derived xenograft model
Oral
30 mg/kg
Once daily for 30 days
To study the effect of PHA-665752 on cetuximab efficacy, results showed that PHA-665752 restored sensitivity to cetuximab
Int J Cancer. 2019 Aug 1;145(3):748-762.
BALB/c nude mice
Peritoneal dissemination model
Intraperitoneal injection
10 mg/kg
Three times per week for 9-11 days or 16-18 days
To evaluate the inhibitory effect of PHA-665752 on peritoneal dissemination of 44As3 and 58As9 cells
Cancer Sci. 2014 May;105(5):528-36.
Nude mice
Pancreatic cancer xenograft model
Intravenous injection
15 mg/kg
Once daily for 21 days
To investigate the effect of PHA-665752 on tumor growth in a pancreatic cancer xenograft model, results showed that the combination of PHA-665752 and TST significantly inhibited tumor growth.
Oncogene. 2016 Sep 8;35(36):4708-18.
Nude mice
GTL-16 tumor xenograft model
Intraperitoneal injection
25 mg/kg or 50 mg/kg
Once daily for 8-10 days
To evaluate the inhibitory effect of PHA-665752 on GTL-16 tumor growth and MET phosphorylation
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