Figure 1. Saracatanib mechanism of action. Saracatinib acts by the
inhibition of the SRC protein, resulting in a reduction of signaling
pathways. This subsequently diminishes RAS activation, ultimately
inhibiting the proliferative activity and the differentiation in
fibroblasts. VEGFR; Vascular Endothelial Growth Factor Receptor. FGFR;
Fibroblast Growth Factor Receptor. PDGFR; Platelet-Derived Growth Factor
Receptor. c-KIT; Tyrosine-protein kinase Kit. FLT-3; FMS-like Tyrosine
Kinase 3. EGFR; Epidermal Growth Factor Receptor. sRC; Sarcoma tyrosine
kinase. MEK; Mitogen-Activated Protein Kinase Kinase. ERK; Extracellular
Signal-Regulated Kinase.
Saracatinib has a larger inhibitory effect than the other two
antifibrotic medications on the expression of various profibrotic genes
induced by TGF-β, like ACTA2, SERPIN1, and COL1A1, according to an in
vitro model research that was conducted with an aim of comparing the
efficacy of Saracatinib with the other approved antifibrotic
medications. In addition, Saracatinib inhibits TGF-Β leading to a change
in many signaling pathways, including the JAK-STAT3, IL6, and IFN-γ. It
also inhibits the alpha-smooth muscle actin (α-SMA) and filamentous
actin (F-actin). All of these inhibitory effects prevent fibroblast
transformation to myofibroblast as well as decrease pulmonary collagen
deposition [32].
In a precision cuts lung slices or PCLS conducted for complementary
purposes, saracatinib had a much better effect than NDB and PFD by
studying an ex vivo model showing reduction in pulmonary fibrosis
and this was confirmed in in vivo mouse models. Therefore, this
study provided an absolute indication that saracatinib is equal or could
be even better than the currently used antifibrotic drugs, PFD and NDB
as an inhibitor of pulmonary fibrosis in experimental models [32],
showing a potential that it could replace both drugs in the future.