Strategies for the design of selective protein kinase inhibitors

Most kinase inhibitors reported so far are designed to bind to a highly conserved ATP binding pocket in a competitive manner. In this case, inhibitors targeting the ATP pocket may crossreact with different kinases, as well as with other proteins that bind ATP, and this may cause undesirable side effects that would limit their clinical usefulness. In addition to the kinase selectivity issues, human ether-a-go-go-related gene (hERG) inhibition could be an obstacle to develop a kinase inhibitor as a safe drug. This paper will review the methods employed in the development of selective kinase inhibitors with several successful examples. These include medicinal chemistry efforts to conquer hERG inhibition problems as sometimes seen in kinase inhibitor programs.