FAK (Focal adhesion kinase), a non-receptor tyrosine kinase, can regulate the cytoskeleton and act as a scaffolding and signaling protein for other adhesion molecules. The expression of FAK and its phosphorylation status show a strong correlation with the invasive phenotype of aggressive human tumors. PF-562271 is a potent and selective inhibitor for FAK and Pyk2 with IC50 values of 1.5nM and 14nM (measured by recombinant kinase assay), respectively, displaying over 100-fold selectivity against the other kinases tested[1]. PF-562271 showed robust inhibition on p-FAK with IC50 of 5nM in an inducible cell-based assay. Oral administration of PF-562271 can inhibit p-FAK in a dose-dependent fashion with calculated EC50 of 93ng/ml in the tumor-bearing mice, which suggesting the pharmacodynamics of this compound. In vitro study showed that PF-562271 had antitumor efficacy or caused tumor regression in multiple human s.c. xenograft models, including BxPC3, LoVo, U87MG, H125, PC3M and BT474, with dose ranging in 25-100mg/kg according to different models[1].
作用机制
PF-562271 can bind in the ATP-binding cleft of FAK and form two of the three H-bonds between PF-562271 and main-chain atoms in the kinase hinge region.[1]
PF-562271 significantly inhibited the osteocrine-induced survival of C4-2B4 cells.
Cancer Res. 2015 Nov 15;75(22):4949-59.
PC3-mm2 cells
0.1 µM
24 h
PF-562271 inhibited FAK-Y397 phosphorylation and significantly reduced the survival of PC3-mm2 cells in soft agar colony formation assays.
Cancer Res. 2015 Nov 15;75(22):4949-59.
human keratinocytes
10 µM
2 h
Inhibited FAK activity, prevented the increase of p-FAK and p-Erk1/2 expression induced by JAM-A knockdown, but did not affect p-JNK expression, and slowed down keratinocyte proliferation and migration.
Cell Death Dis. 2018 Aug 28;9(9):848.
HepG2 cells
2 μM
4 h
To verify whether SCBPE affects HepG2 cell proliferation through the FAK signaling pathway, results showed that PF-562271 alone or in combination with SCBPE significantly increased the cell proliferation inhibition rate.
Drug Des Devel Ther. 2024 Jul 2;18:2745-2760.
human bone marrow-derived MSCs
10 µM
6 h
inhibited FAK phosphorylation and blocked flow-induced COX2 and HO-1 expression
Cell Signal. 2017 Oct;38:1-9.
Mouse GL261 glioma cells
16 nM
72 h
To evaluate the effect of PF-562271 combined with TMZ on cell viability, results showed that the combination significantly increased cell death.
J Neurooncol. 2023 Feb;161(3):593-604.
Primary human GBM CL-3 cells
16 nM
72 h
To evaluate the effect of PF-562271 combined with TMZ on cell viability, results showed that the combination significantly increased cell death.
J Neurooncol. 2023 Feb;161(3):593-604.
Primary human GBM CL-2 cells
16 nM
72 h
To evaluate the effect of PF-562271 combined with TMZ on cell viability, results showed that the combination significantly increased cell death.
J Neurooncol. 2023 Feb;161(3):593-604.
4T1 cells
1 μM
18 h
To investigate the effect of PF-562271 on FAK autophosphorylation in 4T1 cells, results showed that PF-562271 significantly inhibited FAK autophosphorylation.
Breast Cancer Res. 2009;11(5):R68.
NMuMG cells
1 μM
18 h
To investigate the effect of PF-562271 on FAK autophosphorylation in NMuMG cells, results showed that PF-562271 significantly inhibited FAK autophosphorylation.
Breast Cancer Res. 2009;11(5):R68.
PF-562271 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
SCID mice
PCa-118b tumor model
Oral gavage
33 mg/kg
Twice a day for 2 weeks
PF-562271 significantly inhibited the growth of PCa-118b tumors and delayed tumor recurrence when combined with cabozantinib.
Cancer Res. 2015 Nov 15;75(22):4949-59.
Mice
Aortic banding-induced cardiac hypertrophy model
Oral
15 mg/kg
Once daily for 3 weeks
FAK inhibitor PF-562271 significantly reversed aortic banding-induced cardiac hypertrophy and fibrosis in cADAM23-KO mice
J Am Heart Assoc. 2018 Sep 18;7(18):e008604
C57BL/6 mice
C57Bl/6-GL261 glioma model
Oral
50 mg/kg
Once daily for 2 weeks
To evaluate the effect of PF-562271 combined with TMZ on tumor growth and animal survival, results showed that the combination significantly reduced tumor size and invasive margins and increased animal survival.
J Neurooncol. 2023 Feb;161(3):593-604.
Balb/C mice
4T1 tumor model
Oral
50 mg/kg
Daily, for the duration of the experiment
To investigate the effect of PF-562271 on 4T1 tumor growth and lung metastasis, results showed that PF-562271 significantly reduced tumor growth and lung metastasis.
搜索
