Kenneth M. Comess
Polypharmacology in lead discovery programs is increasingly recognized as both an asset and a liability. Lapatinib, for example, is an approved cancer drug that is likely more effective due to targeting both the EGFR and ErbB-2 receptor tyrosine kinase active sites. Unfortunately, targeting the ATP site of protein kinases for drug development often provides an exceptional challenge to selectively inhibit only the kinase(s) of interest and not any of the other 500 - 600 kinases comprising the kinome.
Here we describe use of the unbiased ultra-high throughput technique Affinity Selection/Mass Spectrometry to identify ligands binding to all druggable sites on two targets, the insulin signaling MAP kinase Jnk-1 and the inflammatory kinase p38 alpha.
Ligand characterization by protein NMR, x-ray crystallography, surface plasmon resonance, and biochemical and cell-based assays revealed a novel binding site on these proteins in the MAP insertion region. The ligands to this site on Jnk-1 then were optimized to allow inhibition in functional cellular assays.
This novel site, discovered through affinity-based HTS, provides a new avenue for MAP kinase drug design by significantly restricting the potential selectivity challenge in kinase drug design.
|Click [+] for other articles on||The Market Place for Lab Automation & Screening||The Market Place|