The Masterkey concept

The Masterkey concept is a chemogenomic platform to deal with a large number of potential protein targets with increased efficiency in lead generation delivering target-specific molecules amenable to parallel optimization towards potential pre-clinical candidates. The core elements of the kinase-biased Masterkey concept are so-called privileged structures that emerge from a sophisticated molecular design and optimization process that encode for a target family-wide structural commonality in ligand binding. The combination of a kinase family-wide imprinted commonality with additional structural fragments in the molecular periphery of a once established privileged structure allows to synthesize not only highly active, but, more importantly, also selective kinase inhibitors.

The available structural information provides profound insight in kinases at a molecular level and facilitates the design of potent and selective antagonists. In order to introduce the Masterkey concept based on kinase-directed privileged structures, common structure determinants, as well as the most discriminating attributes of ATP binding sites need to be highlighted. The observations from structural biology that on one hand the ATP binding pocket displays common structural features throughout the family, and on the other hand the adenosine-binding region is flanked by cavities that are aligned with residues that, from an evolutionary point of view considerably diverged, provide the ideal precondition for a target family-biased Masterkey concept. The conserved part of the ATP-binding pocket is the negative imprint for the design of a privileged structure, while specificity-mediating peripheral groups attached to the underlying privileged structure target the flanking cavities, markedly differing in size, shape, and surface properties among different kinases.