Structural analysis of PI3-kinase isoforms: identification of residues enabling selective inhibition by small molecule ATP-competitive inhibitors |
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| Authors: | Zvelebil Marketa J Waterfield Michael D Shuttleworth Stephen J |
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| Institution: | aThe Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK;bLudwig Institute for Cancer Research, The Courtauld Building, 91 Riding House Street, London W1W 7BS, UK;cPIramed Ltd., 957 Buckingham Avenue, Slough, SL1 4NL, UK |
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| Abstract: | A series of small molecule, ATP-competitive phosphoinositide 3-kinase inhibitors have been examined in homology models of the four class I isoforms, p110α, p110β, p110δ and p110γ. This analysis provided an insight into the mode of binding of these inhibitors to the hinge and to other key regions of the ATP binding site in each of the four subtypes. Significantly, residues were identified that differ between these proteins, and which help explain the isoform-selective inhibition profiles of the compounds. |
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| Keywords: | PI3-Kinase isoforms Selective inhibition ATP-competitive inhibitors Molecular modelling Docking |
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