PD168393

PD168393 is an irreversible kinase inhibitor of epidermal growth factor receptor (EGFR) with IC50 value of 0.70±0.09 nM and continued to have suppressed kinase activity after 8 hr in compound-free medium.[1]
The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is the cell-surface receptor for members of the epidermal growth factor family (EGF-family) of extracellular protein ligands. Upon activation by its growth factor ligands, EGFR undergoes a transition from an inactive monomeric form to an active homodimer.[2] In addition to forming homodimers after ligand binding, EGFR may pair with another member of the ErbB receptor family to create an activated heterodimer. EGFR dimerization stimulates its intrinsic intracellular protein-tyrosine kinase activity. [3] As a result, autophosphorylation of several tyrosine (Y) residues in the C-terminal domain of EGFR occurs which elicits downstream activation and signaling by several other proteins that associate with the phosphorylated tyrosines through their own phosphotyrosine-binding SH2 domains. These downstream signaling proteins initiate several signal transduction cascades, principally the MAPK, Akt and JNK pathways, leading to DNA synthesis and cell proliferation.[4]
Mutations that lead to EGFR overexpression or overactivity have been associated with a number of cancers, thus many therapeutic approaches are aimed at the EGFR now. PD 168393 can poss a high specificity toward the EGFr with Cys-773 which  inhibit the EGFR tyrosine kinase, which is on the cytoplasmic side of the receptor. Without kinase activity, EGFR is unable to activate itself, which is a prerequisite for binding of downstream adaptor proteins. Ostensibly by halting the signaling cascade in cells that rely on this pathway for growth, tumor proliferation and migration is diminished.[5]
PD168393 can enhance paclitaxel-induced DNA fragmentation, sub-G1 fraction accumulation, mitochondrial membrane dysfunction, cytochrome C release, caspase-3 activation and eventually apoptosis in vitro by MTT assay and median-effect analysis. In conclusion, the combination of paclitaxel and PD168393 produced a profound synergistic growth inhibition of AIPC cells,resulting in clinical benefits and warrants further investigation.[6]
References:
1.David W. Fry. et al. Specific, irreversible inactivation of the epidermal growth factor receptor and erbB2, by a new class of tyrosine kinase inhibitor. Pharmacology. Proc Natl Acad Sci U S A. 1998, 95(20): 12022–12027.
2.Yosef Yarden and Joseph Schlessinger. "Epidermal Growth-Factor Induces Rapid, Reversible Aggregation of the Purified Epidermal Growth-Factor Receptor". Biochemistry 1987,26 (5): 1443–1451.
3.Downward J, Parker P, Waterfield MD. "Autophosphorylation sites on the epidermal growth factor receptor". Nature 1984,311 (5985): 483–5.
4.Oda K, Matsuoka Y, Funahashi A, Kitano H. "A comprehensive pathway map of epidermal growth factor receptor signaling". Mol. Syst. Biol,2005,1 (1).
5.Olive DM ."Quantitative  methods  for  the  analysis  of  protein Phosphorylation In drug development". Expert Rev Proteomics2004, 1(3):327–41.
6.Pu YS1, Hsieh MW, et al. Epidermal growth factor receptor inhibitor (PD168393) potentiates cytotoxic effects of paclitaxel against androgen-independent prostate cancer cells. Biochem Pharmacol.