Designing heterocyclic selective kinase inhibitors: from concept to new drug candidates

Kinases represent one of the most popular and promising target class in drug discovery. Success in finding new therapeutics will depend on the validation of the kinase choosen with respect to the disease of interest, and on the ability of chemists to design and synthesize inhibitors which are selective for this particular kinase. One of the most powerful validation tool for kinases is the Analogue-Sensitive Kinase Allele ( ASKA) technology, where chemists and biologists have engineered modified kinases and inhibitors by generating functionally active kinase mutants which are specifically inhibited by a chemically modified inhibitor, thus allowing to study specific responses in knock-in animals. The design of selective, ATP competitive kinase inhibitors has been succesfully achieved by combining different technologies like cpomputational chemistry, structure-based design and combinatorial chemistry as illustrated by the discovery of AS602801, a potent and selective JNK inhibitor with therapeutic potential in MS and fibrosis. The exploration of non ATP-competitive inhibitors is also very promising, as illustrated by the case of MEK inhibitors which show strong interest as anti-cancer agents. In the future, the rationale design of selective kinase inhibitors will move to the design of compounds that will induce a selective perturbation of cell regulation, where kinases play a critical role.