Divergent modulation of Src-family kinase regulatory interactions with ATP-competitive inhibitors.

Multidomain protein kinases, central controllers of signal transduction, use regulatory domains to modulate catalytic activity in a complex cellular environment. Additionally, these domains regulate noncatalytic functions, including cellular localization and protein-protein interactions. Src-family kinases (SFKs) are promising therapeutic targets for a number of diseases and are an excellent model for studying the regulation of multidomain kinases.

Protein kinase affinity reagents based on a 5-aminoindazole scaffold.

Affinity reagents that target protein kinases are powerful tools for signal transduction research. Here, we describe a general set of kinase ligands based on a 5-aminoindazole scaffold. This scaffold can readily be derivatized with diverse binding elements and immobilized analogs allow selective enrichment of protein kinases from complex mixtures.

Biochemical mechanisms of resistance to small-molecule protein kinase inhibitors.

Protein kinases have emerged as one of the most frequently targeted families of proteins in drug discovery. While the development of small-molecule inhibitors that have the potency and selectivity necessary to be effective cancer drugs is still a formidable challenge, there have been several notable successes in this area over the past decade. However, in the course of the clinical use of these inhibitors, it has become apparent that drug resistance is a recurring problem.

Chemical genomic and proteomic methods for determining kinase inhibitor selectivity.

The clinical success of the Bcr-Abl tyrosine kinase inhibitor Gleevec((R)) and the recent clinical approval of a number of small molecule drugs that target protein kinases have intensified the search for novel protein kinase inhibitors. Since most small molecule kinase inhibitors target the highly conserved ATP-binding pocket of this enzyme family, the target selectivity of these molecules is a major concern. Due to the large size of the human kinome, it is a formidable challenge to determine the absolute specificity of a given protein kinase inhibitor, but recent technological developments have made substantial progress in achieving this goal.