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.