Signals of disease | Nature

You have full access to this article via your institution. Download PDF Protein kinases are linked to numerous disease states, including cancer, arthritis, diabetes, cardiovascular diseases

and neurological disorders. Gleevec from Novartis was the first compound active against a kinase (the Abl kinase) to be approved as a treatment — for certain gastrointestinal tumours and

chronic myeloid leukaemia. R&D Systems' Phospho-MAPK array tracks phosphorylated kinases. Credit: R&D SYSTEMS The market for kinases is large. “More than 25% of new drugs being

developed today are based on kinase technology,” says Jeff Linton, president of Upstate of Charlottesville, Virginia, which offers one of the largest collections of kinases. A flagship of

Upstate's operation is its KinaseProfiler service, run from Dundee in Scotland. This provides quantitative characterization of compounds against an ever-expanding panel of human protein

kinases in a direct radiometric assay. The panel currently contains around 230 kinases, almost 50% of the total number of human kinases in the genome. A new focus for Upstate is the

addition of naturally occurring mutant kinases as they are identified. Attention is also focusing on the newly emerging Gleevec-resistant mutants of Abl, and mutant forms of other kinases

including the epithelial growth factor (EGF) receptor, as these mutations can alter an inhibitor's efficacy. One of these mutations involves a single ‘gatekeeper’ amino acid. Mutations

in this amino acid can prevent therapeutic compounds from binding effectively without affecting the enzyme's activity. “The search is on for successful inhibitors that are not sensitive

to changes at the gatekeeper site,” says Steve Davies, director of Upstate's drug discovery segment. Upstate is helping this search by adding eight different mutant kinases to their

portfolio, including ones for Kit, EGFR, Abl, Flt3 and p38/SAPK2a — and, says Davies, there are more in the pipeline. A highly specific set of anti-kinase antibodies makes up R&D

Systems' Proteome Profiler Phospho-MAPK Array. This allows analysis of the phosphorylation status of 19 key signalling proteins, including members of all three major families of

mitogen-activated protein kinases — the extracellular signal-regulated kinases, c-Jun N-terminal kinases, and the p38 kinases. These enzymes play essential roles in numerous signalling

pathways that underlie cell function and disease. Signalling pathway analysis products from Beckman Coulter of Fullerton, California, are also devoted to looking at intracellular activated

(phosphorylated) kinases. One strength is that these reagents can be used on many different types of specimen including whole blood, and can resolve activated and inactivated kinases in

whole blood cells, according to Michel Herbert, marketing manager for Beckman Coulter. P.M. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Signals of

disease. _Nature_ 438, 702 (2005). https://doi.org/10.1038/438702a Download citation * Published: 30 November 2005 * Issue Date: 01 December 2005 * DOI: https://doi.org/10.1038/438702a SHARE

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