Protein kinase inhibition: different approaches to selective inhibitor design.

Protein kinases represent a large family of enzymes involved in regulating complex molecular machineries that control many cellular functions, from survival and proliferation to apoptosis. Abnormal protein kinase activity has been involved in a variety of pathophysiologic states, including cancer, inflammatory and autoimmune disorders, and cardiac diseases, and protein kinases have become one of the major therapeutical targets of the past 10 years. The major problem associated with ATP-competitive kinase inhibition is target specificity, since many other enzymes, kinases and not-kinases alike, utilize ATP: less specific inhibitors would be expected to exhibit undesirable toxicities that would limit their potential utility as therapeutic agents. The purpose of this review is to offer the reader an idea of the evolution of the methodologies utilized in the quest for selective kinase inhibitors, from the more traditional, screening-based methods to the newer technology of chemogenomics, proteomics and chemical genetics.