Protein kinases are enzymes that phosphorylate substrate proteins at specified residues such as serine, threonine, and tyrosine. The phosphorylation of the substrate protein initiates a cascade, that in turn, modulates the transcription of a gene or set of genes. Kinases play pivotal roles in modulating diverse cellular activities, including growth, differentiation, metabolism, adhesion, motility, and death, and have been implicated as important mediators of certain forms of cancer.
Kinases, therefore, represent key druggable target proteins. The initial realization that most kinases possess highly conserved catalytic domains initially made kinase targets ideally suited for compound screening via focused chemical libraries in which the library compounds were specifically created to bind to the catalytic (hinge) regions.
Despite the slightly higher costs generally associated with the design and synthesis of such focused libraries compared to large and diverse compound collections, true savings can be gained as a result of shortened project cycles coupled with the reduced costs of screening, storage, and quality control of a smaller screening library.
The increasing wealth of structural data available along with a number of new techniques such as in silico design has enabled the continual development of kinase-focused collections, providing increasingly more sophisticated chemical structures. One of the key benefits of this is that the current range of SoftFocus kinase libraries has been designed to target additional binding modes to those involving the hinge region; most notably the DFG-out binding mode and the novel binding mode first observed in the kinase PIM-1.