The binding mechanism of a new class of lipid-competitive, ATP non-competitive, p110α isoform-selective PI3K (phosphoinositide 3-kinase) inhibitors has been elucidated. Using the novel technique of isoform reciprocal mutagenesis of non-conserved amino acids in the p110α and p110β isoforms, we have identified three unique binding mechanisms for the p110α-selective inhibitors PIK-75, A-66S and J-32. Each of the inhibitor's p110α-isoform-selective binding was found to be due to interactions with different amino acids within p110. The PIK-75 interaction bound the non-conserved region 2 amino acid p110α Ser773, A-66S bound the region 1 non-conserved amino acid p110α Gln859, and J-32 binding had an indirect interaction with Lys776 and Ile771. The isoform reciprocal mutagenesis technique is shown to be an important analytical tool for the rational design of isoform-selective inhibitors.
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Research Article|
May 29 2012
Definition of the binding mode of a new class of phosphoinositide 3-kinase α-selective inhibitors using in vitro mutagenesis of non-conserved amino acids and kinetic analysis
Zhaohua Zheng;
Zhaohua Zheng
*Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria 3052, Australia
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Syazwani I. Amran;
Syazwani I. Amran
*Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria 3052, Australia
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Jiuxiang Zhu;
Jiuxiang Zhu
†The Ludwig Centre for Cancer Genetics and Therapeutics, The Howard Hughes Medical Institute, and The Johns Hopkins Kimmel Cancer Centre, Baltimore, MD, U.S.A.
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Oleg Schmidt-Kittler;
Oleg Schmidt-Kittler
†The Ludwig Centre for Cancer Genetics and Therapeutics, The Howard Hughes Medical Institute, and The Johns Hopkins Kimmel Cancer Centre, Baltimore, MD, U.S.A.
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Kenneth W. Kinzler;
Kenneth W. Kinzler
1
†The Ludwig Centre for Cancer Genetics and Therapeutics, The Howard Hughes Medical Institute, and The Johns Hopkins Kimmel Cancer Centre, Baltimore, MD, U.S.A.
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Bert Vogelstein;
Bert Vogelstein
1
†The Ludwig Centre for Cancer Genetics and Therapeutics, The Howard Hughes Medical Institute, and The Johns Hopkins Kimmel Cancer Centre, Baltimore, MD, U.S.A.
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Peter R. Shepherd;
Peter R. Shepherd
2
‡Department of Molecular Medicine and Pathology and Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand
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Philip E. Thompson;
Philip E. Thompson
*Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria 3052, Australia
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Ian G. Jennings
Ian G. Jennings
3
*Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria 3052, Australia
3To whom correspondence should be addressed (email Ian.Jennings@monash.edu.au).
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Publisher: Portland Press Ltd
Received:
March 23 2012
Revision Received:
April 13 2012
Accepted:
April 13 2012
Accepted Manuscript online:
April 13 2012
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem J (2012) 444 (3): 529–535.
Article history
Received:
March 23 2012
Revision Received:
April 13 2012
Accepted:
April 13 2012
Accepted Manuscript online:
April 13 2012
Citation
Zhaohua Zheng, Syazwani I. Amran, Jiuxiang Zhu, Oleg Schmidt-Kittler, Kenneth W. Kinzler, Bert Vogelstein, Peter R. Shepherd, Philip E. Thompson, Ian G. Jennings; Definition of the binding mode of a new class of phosphoinositide 3-kinase α-selective inhibitors using in vitro mutagenesis of non-conserved amino acids and kinetic analysis. Biochem J 15 June 2012; 444 (3): 529–535. doi: https://doi.org/10.1042/BJ20120499
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