Article

A General Framework for Inhibitor Resistance in Protein Kinases

Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy.
Chemistry & biology (Impact Factor: 6.59). 08/2011; 18(8):966-75. DOI: 10.1016/j.chembiol.2011.04.013
Source: PubMed

ABSTRACT Protein kinases control virtually every aspect of normal and pathological cell physiology and are considered ideal targets for drug discovery. Most kinase inhibitors target the ATP binding site and interact with residue of a hinge loop connecting the small and large lobes of the kinase scaffold. Resistance to kinase inhibitors emerges during clinical treatment or as a result of in vitro selection approaches. Mutations conferring resistance to ATP site inhibitors often affect residues that line the ATP binding site and therefore contribute to selective inhibitor binding. Here, we show that mutations at two specific positions in the hinge loop, distinct from the previously characterized "gatekeeper," have general adverse effects on inhibitor sensitivity in six distantly related kinases, usually without consequences on kinase activity. Our results uncover a unifying mechanism of inhibitor resistance of protein kinases that might have widespread significance for drug target validation and clinical practice.

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Available from: Fabrizio Villa, Oct 16, 2014
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    • "Inhibitor resistance has not yet been described for Cdks, so we sought to design it de novo. Generation of inhibitor resistance in protein kinases by mutation or selection using genetic screens has been achieved for various kinases, including p38, c-Abl, Aurora A, Aurora B, Plk1, c-Src, PAK5, Phkg, CK1d, and haspin (Azam et al., 2003; Balzano et al., 2011; Bradeen et al., 2006; Eyers et al., 1998; Girdler et al., 2008; Gum et al., 1998; Scutt et al., 2009), implying that inhibitor resistance might be achievable for any protein kinase. "
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    • "Inhibitor resistance has not yet been described for Cdks, so we sought to design it de novo. Generation of inhibitor resistance in protein kinases by mutation or selection using genetic screens has been achieved for various kinases, including p38, c-Abl, Aurora A, Aurora B, Plk1, c-Src, PAK5, Phkg, CK1d, and haspin (Azam et al., 2003; Balzano et al., 2011; Bradeen et al., 2006; Eyers et al., 1998; Girdler et al., 2008; Gum et al., 1998; Scutt et al., 2009), implying that inhibitor resistance might be achievable for any protein kinase. "
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