Protein Kinases As Therapeutic Targets – Imatinib Mesylate (Gleevec)
Protein kinases play an important role in signaling pathways that regulate cell functions like metabolism, cell adhesion, vascular function, angiogenesis, cell cycle progression etc. It has been found that in pathological conditions; activity of protein kinase is deregulated, prompting inhibition of the same worthy of evaluation as treatment option. Compounds that inhibit tyrosine kinases are being increasingly considered potent cancer therapeutic agents. A classic example of success is the tyrosine kinase inhibitor, Gleevec (Imatinib mesylate) used in treatment of chronic myelogenous leukemia (CML).
Some of the approaches for regulation of kinase gene expression include:
- Inhibiting post-transcriptional processing of mRNA.
- Inhibition of kinase activity.
- Monoclonal antibodies to inhibit receptor linked kinases.
The kinase inhibitors apart from acting on kinases and regulation of the same may actually provide other therapeutic agents more time to become effective. The synergistic action of protein kinases with current treatments is promising as demonstrated by results obtained during testing and clinical trials.
Imatinib Mesylate, Gleevec
- Gleevec is an inhibitor of specific tyrosine kinases that targets platelet-derived growth factor (PDGF) receptor.
- The kinase in effect prevents the formation of a product formed by the fusion of PDGF and Philadelphia (Ph) chromosome (expressed in CML).
- A similar effect of Gleevec has also been observed on gastrointestinal stromal tumors. The drug here inhibits PDGF from forming a product with c-kit (CD117, over expressed in gastrointestinal stromal tumors).
- Food and Drug Administration has approved the use of Imatinib for treatment of CML that does not respond to interferon therapy and in treatment of gastrointestinal stromal tumors.
About Protein Kinases
Protein kinases are enzymes that modify a protein chemically by the addition of a phosphate group. The transfer of a phosphate group is usually to one of the three amino acids (serine, threonine, and tyrosine) that have a free hydroxyl group. The addition of phosphate group activates protein leading to change in enzyme activity, location in cell, or inter-protein associations. Majority of cellular pathways and signal transductions in the human cell is regulated by protein kinases. There are about 500 protein kinase genes in the human genome.