Protein Kinase Inhibitors for Clinical Targeted Cancer Treatment

Abstract

Protein kinases are defined by their ability to catalyse the transfer of the terminal phosphate of ATP to substrates that usually contain a serine, threonine or tyrosine residue. They typically share a conserved arrangement of secondary structure elements that are arranged into 12 sub domains that fold into a bi-lobed catalytic core structure with ATP binding in a deep cleft located between the lobes. ATP binds in the cleft with the adenine ring forming hydrogen bonds with the kinase ‘hinge’ the segment that connects the aminoand carboxyterminal kinase domains. The highly conserved DFG-motif position in A-loop along with catalytic Lys from β3 strand usually determines kinase activity. Deregulation of protein kinase activities, particularly dominant kinase mutations (such as BRAF V600E in A-loop, and JAK2 V617F in the auto-inhibitory pseudokinase domain), may result in a number of conditions such as cancer, inflammatory or infectious diseases, diabetes, degenerative nerve diseases, and cardiovascular disorders. There are 518 protein kinases and about 20 lipid-modifying kinases encoded by the human genome [1,2], and a much larger proportion of additional kinases are present in parasite, bacterial, fungal, and viral genomes that are susceptible to exploitation as drug targets. Cancer is global leading causes of death which is responsible for about 25% of all deaths and features with 0.5% annual diagnostic rate. The National Institutes of Health (NIH) estimates that the overall costs of cancer in 2007 were $226.8 billion.