Protein Kinase Inhibitors

Protein kinase inhibitors are the front runners in signal transduction therapy, because the catalytic sites of enzymes are easier targets for drug design than protein–protein interaction domains. It has been recognized that protein tyrosine kinases comprise a major fraction of the signaling elements on whose activities the survival of the cancer cell is highly dependent. A number of serine/threonine kinases have also been found to play central roles in cancer. The first group of synthetic tyrphostins/TKIs synthesized was the benzene malononitrile tyrphostins. Their interaction with the EGFR or PDGFR reduces the binding affinity for both ATP and substrate, causing a reduction in the catalytic activity of the enzyme, thus making them an allosteric inhibitor. Cancer cells are susceptible to agents like cis-Platin (CDDP) and to pro-apoptotic ligands like FasL. As a cancer progresses, the potentiated sensitivity to stress is shielded by a massive anti-apoptotic signaling network. This is probably why PTK inhibitors synergize with cytotoxic drugs or pro-apoptotic proteins. The enhanced activity of PTKs is also related to diseases other than cancer. It has been suggested that EGFR kinase inhibitors can be used as topical agents to treat these conditions. Ser/Thr kinases have essential roles in cell proliferation and anti-apoptotic signaling. The activities of these kinases can be enhanced in cancerous cells by the synergistic action of enhanced upstream PTKs combined with the inactivation of downstream negative regulators.