Platelet-derived growth factor receptors (PDGF-R) are a kind of tyrosine kinase receptor on the cell surface of the PDGF family. Specifically, PDGF subunit-A and-B are important factors in regulating cell proliferation, cell differentiation, and many diseases including cancer. Besides, PDGF-R has two forms, α and β are free and different gene coding. Ras/MAPK, PI-3K, and PLCγ pathways are keys downstream mediators of PDGFR signaling. The adaptor protein Grb2 forms a complex with SOS through the Grb2 SH3 domain. Thus, this allows interaction with Ras and GTP exchange on GDP.
Initiating PDGF signal transduction is usually through binding growth factors to the extracellular ligand-binding domain of the receptor. Furthermore, this results in dimerization of the receptor and subsequent phosphorylation of tyrosine residues in the intracellular domain. Meanwhile, PDGF signaling is relevant to SHP-2 tyrosine phosphatase. Nonetheless, it binds to PDGFR through its SH2 domain and dephosphorylates the receptor and its substrate. PDGF signaling pathway is in human PAH and plays an important role in BMPR2 regulation. Increased PDGFR activity is relevant to various pathological conditions, including cancer, vascular disease, and various fibrosis conditions. Today, we will introduce an inhaled Pdgfr kinase inhibitor, Seralutinib.
Seralutinib is an Inhaled Pdgfr Kinase Inhibitor.
First of all, Seralutinib (GB002) is a potent inhaled PDGFRα/β inhibitor. Importantly, Seralutinib inhibits lung PDGFRα/β phosphorylation and induces lung BMPR2 protein expression in a dose- and time-dependent manner in healthy Sprague Dawley rats. Particularly, Seralutinib has the potential for pulmonary arterial hypertension research.
In the second place, Seralutinib (two-week treatment, delivered by inhalation) significantly reduces right ventricular systolic pressure and mean pulmonary artery pressure in rats. Obviously, hemodynamic changes were accompanied by reduced pulmonary arteriole muscularization. Interestingly, it also has restoration of BMPR2 protein expression in the lung lobes in Seralutinib-treated animals. In parallel, it decreased plasma levels of NT-proBNP and PDGF-B, along with modulation of pro-inflammatory cytokines.
Last but not the least, Seralutinib significantly decreased pulmonary arteriolar muscularization and improved disease biomarkers in the SU5416 hypoxia rat model.
All in all, Seralutinib is a potent inhaled PDGFRα/β inhibitor.