PD-089828 is an Inhibitor of FGFR-1, PDGFR-β, EGFR and c-Src Tyrosine Kinase

Protein tyrosine kinases comprise a group of enzymes. They catalyze the phosphorylation of certain proteins on specific tyrosine residues. The growth factor receptor tyrosine kinases are a subfamily. The kinases are activated on the high-affinity binding of growth factors to their cognate receptors. Members of this subfamily include PDGFR α and β isoforms, FGFR, and EGFR.  c-Src is a non-receptor tyrosine kinase. It binds via its Src homology-2 (SH2) domain and becomes phosphorylated by the PDGFR. Thus, the process of linking extracellular signals present at the cell membrane with changes in gene expression at the nucleus is a common mechanism for transducing cellular signaling events, such as mitogenesis, differentiation, migration, and cell survival. PD-089828, a protein tyrosine kinase inhibitor, is ATP competitive for PDGFR, EGFR, and FGFR tyrosine kinases. In addition, it is uniquely non-competitive for c-Src tyrosine kinase.

PD-089828 is an ATP competitive inhibitor of FGFR-1, PDGFR-β, and EGFR and a noncompetitive inhibitor of c-Src tyrosine kinase, with long-lasting cellular activity.

PD-089828 prolongs inhibition of a variety of growth factor-mediated cellular functions whose effects are reversible. It inhibits PDGFR autophosphorylation with an IC₅₀ of 0.82 µM. Meanwhile, PD-089828 inhibits EGFR autophosphorylation with an IC₅₀ value of 10.9 µM. In A121(p) cells, PD 089828 potently inhibits the phosphorylation of FGFR-1 with an IC₅₀ value of 0.63 µM. It also produces a concentration-related inhibition of serum-stimulated cell growth with an IC₅₀ value of 1.8 µM. Furthermore, PD-089828 inhibits increases in DNA synthesis stimulated by all three growth factors, with IC₅₀ values of 0.8 for PDGF-, 1.7 for EGF- and 0.48 µM for bFGF-induced mitogenesis. In addition, it also inhibits MAPK with an IC₅₀ of 7.1 µM.

PD-089828 is a nonselective inhibitor of protein tyrosine kinases with long-lasting cellular activity. It displays an ATP competitive inhibitor of PDGFR-β, FGFR-1, and EGFR tyrosine kinases but a noncompetitive inhibitor of c-Src kinase. PD-089828 is a broadly active inhibitor of protein tyrosine kinases that makes it attractive for use in a number of diseases, such as cancer, atherosclerosis, and restenosis.

Reference:

Dahring TK, et al. J Pharmacol Exp Ther. 1997 Jun;281(3):1446-56.