Native kinase profiling

By Dr Matt Wilkinson

- Last updated on GMT

Related tags Signal transduction

ActivX has launched a new profiling platform, which the company
claims allows the functional analysis of twice the number of
protein kinases than competing systems.

The KiNativ platform has been launched to address the problem of designing safe and effective kinase inhibitors by allowing the screening of over 450 kinases.

The technique will find applications in drug target discovery, lead optimisation, toxicology and clinical development.

Protein kinases represent the largest family of mammalian enzymes and regulate cellular signalling pathways by modifying the activity of specific proteins by phosphorylation.

There are over 500 human protein kinases which all share striking structural similarities.

While most kinase screening platforms are based on the creation of artificial constructs of protein kinases in recombinant assay systems, KiNativ uses what they call 'native kinases'.

The approach allows the assays to be conducted on kinases in real biological samples, labelling them in situ to give in vivo results that have much higher relevance to real-life patients.

"KiNativ's results give a much more accurate assessment of kinase activity and inhibition than can be achieved in other kinase profiling systems.

The in vivo relevance of the data is much higher," said Dr John Kozarich, president of ActivX. The kinase inhibitor market has been predicted by Pharmaprojects to grow to $58.6bn by 2010, with GlaxoSmithKline's Tykerb (lapatinib) the latest inhibitor to have been approved by the US Food and Drug Administration (FDA).

While the majority of kinase inhibitors such as Tykerb, AstraZeneca's Iressa (gefitinib) and Bristol-Myers Squibb's Sprycel (dasatinib) all focus on various different cancer indications, other drug candidates have targeted kinases' role in Alzheimer's , diabetes and arthritis .

The problems involved in designing effective inhibitors are highlighted by the recent failure of Onyx' and Bayer's Nexavar (sorafenib) in a skin cancer trial.

While the drug is already approved for use against kidney cancer the drug failed to show a high enough efficacy against skin melanoma.

" Profiling a drug broadly and accurately against as many kinases as possible is the Holy Grail for kinase profiling technologies.

The best profiling platforms claim assays for 220 or so kinases, well short of the 500 known human kinases," said Kozarich.

"KiNativ's profiling capability currently stands at around 430 kinases and represents a paradigm shift in how kinase activity and inhibitor selectivity will be determined in the future."

The new platform uses biotinylated acyl phosphates of ATP or ADP that irreversibly react with the kinases.

The labelled fragments can then be sequenced and analysed by LC-MS/MS (liquid chromatography - tandem mass spectrometry).

This allows not only the determination of which kinases are present in the biological sample and their relative abundance, but also competition studies between probes and inhibitors to determine inhibitor potency.

"KiNativ will work in any species since the technology is based on characteristics that are shared by all kinases, human or otherwise.

This greatly simplifies data correlation from animal experiments to human studies," said Kozarich.

Related topics Preclinical Research

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