FAK (Focal adhesion kinase), a non-receptor tyrosine kinase, can regulate cell migration, proliferation and survival through regulation on integrin and growth factor signaling pathways. PF-573228 is a selective FAK inhibitor with IC50 value of 4nM (measured by the purified recombinant catalytic fragment of FAK). Treatment with PF-573228 showed cellular FAK inhibition with IC50 of 11nM in A431 cells, and caused dose-dependent inhibition of p-FAK-Y397 with IC50 value of 100nM, 50nM, 300nM, 30nM and 500nM for PC3, SKOV-3, L3.6p1, F-G and MDCK cells. The decrease of paxillin, the downstream substrate of FAK, on its Tyr31 site was achieved by 1μM PF-573228 within 15min, showing the FAK signaling inhibition by PF-573228. Also a dose-dependent decrease by PF-573228 in FAK phosphorylation within paxillin-containing focal adhesions can be observed at concentration ranging in 0.3-3μM in REF52 cells. Pre-treatment with PF-573228 for 30min before 10% serum or fibronectin for 6h caused inhibition of serum- or fibronectin-stimulated migration of REF52 cells at concentration of 1μM with 80% p-FAK inhibition, but the random migration of REF52 cells was observed at concentration up to 10μM[1]. Inhibition of FAK by intraperitoneal injection of 50 mg/kg PF-573228 reduced signaling cascade of fibroblast migration in bleomycin-challenged mice[2].
作用机制
PF-573228 is a competitive inhibitor of ATP with specificity for FAK family protein-tyrosine kinases.[1]
PF-573228 细胞实验
Cell Line
Concentration
Treated Time
Description
References
HKC-8 cells
50 ng/ml
10 min
PF-573228 inhibited FAK signaling, abolished TNC-triggered FAK and ERK1/2 activation, and suppressed fibronectin and α-SMA expression.
Kidney Int. 2020 May;97(5):1017-1031.
NRK-52E cells
10 µM
2 h
PF-573228 inhibits FAK activity, resulting in fine cortical stress fibers and reduced LMO7 association with cortical stress fibers.
Cells. 2022 Nov 28;11(23):3805.
Retinal Ganglion Cells
10 µM
24 h
To investigate the effect of the FAK inhibitor PF-573228 on BAX translocation in retinal ganglion cells. Results showed that PF-573228 induced BAX translocation after 24 h, but the percentage of translocated cells was lower compared to optic nerve injury.
Mol Neurodegener. 2023 Sep 26;18(1):67.
PF-573228 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Acute kidney injury to chronic kidney disease model
To evaluate the therapeutic effect of PF-573228 on skin fibrosis, results showed that PF-573228 significantly reduced scar formation.
Nat Med. 2011 Dec 11;18(1):148-52
Mice
Diabetic breast cancer model
Subcutaneous injection
50 µM
Once daily for 7 weeks
Inhibition of FAK activity reduces tumor progression in diabetic mice without influencing tumor ECM stiffness.
Sci Adv. 2022 Nov 16;8(46):eabo1673
Mice
Optic Nerve Crush Model
Intravitreal Injection
10 µM – 25 mM,1 μL
Single injection, 24 hours
To investigate the effect of the FAK inhibitor PF-573228 on BAX translocation in the optic nerve crush model. Results showed that PF-573228 induced BAX translocation after 24 hours, but the percentage of translocated cells was lower compared to optic nerve injury.
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