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AKT crystal structure and AKT-specific inhibitors

Oncogene volume 24, pages 7493–7501 (2005)Cite this article

Abstract

AKT kinases are attractive targets for small molecule drug discovery because of their key role in tumor cell survival/proliferation and their overexpression/activation in many human cancers. This review summarizes studies that support the rationale for targeting AKT kinases in new drug discovery efforts. Structural features of AKT kinase in its inactive and active states, as determined by crystal structure analysis, are described. Recent efforts in the development and biological evaluation of small molecule inhibitors of AKT, and the challenges remaining are summarized. Inhibitors targeting the ATP binding site, PH domain and protein substrate binding site, as well as isoform selective allosteric inhibitors are reviewed. Structure-based design using PKA mutants as surrogates and computer modeling in the discovery of selective inhibitors is discussed. The issues and challenges facing the development of different classes of inhibitors as therapeutics are also discussed.

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Acknowledgements

We thank Drs Tin-Yau Chan and Jose Duca for help in the preparation of figures and our colleagues in the AKT project team for stimulating discussions.

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Authors and Affiliations

  1. Department of Tumor Biology, Schering-Plough Research Institute, 2015, Galloping Hill Road, Kenilworth, 07033, NJ, USA

    Chandra C Kumar

  2. Department of Structural Chemistry, Schering-Plough Research Institute, 2015, Galloping Hill Road, Kenilworth, 07033, NJ, USA

    Vincent Madison

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Correspondence to Chandra C Kumar.

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Kumar, C., Madison, V. AKT crystal structure and AKT-specific inhibitors. Oncogene 24, 7493–7501 (2005). https://doi.org/10.1038/sj.onc.1209087

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