Inhibitor binding leads to pre-activation of two kinases according to papers published online at Nature Chemical Biology and Nature Structural & Molecular Biology. The surprising finding may have important implications for drug discovery.
Kinases, which are a type of enzyme, are often 'primed' for full activity by the addition of small chemical groups called phosphates. Kinase inhibitors, used clinically to treat cancer, function by blocking kinase activity. As a result, it was unexpected when an inhibitor of the cancer-associated kinase Akt was found to cause the 'priming' phosphates to be added. Using chemical tools to look closely at this phenomenon, Kevan Shokat and colleagues find that binding of the Akt inhibitor is directly responsible for this increased phosphorylation. Peter Parker and colleagues find a similar effect with the related kinase PKCε - inhibitor binding directly triggers priming phosphorylation. Since, as discussed in an accompanying commentary by Stephen Frye and Gary Johnson, it may not be desirable to have drugs that increase the activity 'readiness' of the kinases they are designed to inhibit, these results have important implications for drug discovery. Author contacts: Kevan Shokat, (University of California, San Francisco, CA, USA)
E-mail: shokat@cmp.ucsf.edu Peter Parker (Cancer Research UK, London, UK)
E-mail: peter.parker@cancer.org.uk Stephen Frye (University of North Carolina, Chapel Hill, NC, USA)
E-mail: sfrye@email.unc.edu Abstracts available online:
Abstract 1.
Abstract 2.
Abstract 3. (C) Nature Chemical Biology press release. (C) Nature Structural & Molecular Biology press release.
Message posted by: Trevor M. D'Souza
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