title: AKT crystal structure and AKT-specific inhibitors.
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.
authors.affiliation: Department of Tumor Biology, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA. chandra.kumar@spcorp.com
authors.forename: Chandra C
authors.initials: CC
authors.lastname: Kumar
authors.forename: Vincent
authors.initials: V
authors.lastname: Madison
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001665:Binding Sites; D003460:Crystallization; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008956:Models, Chemical; D009369:Neoplasms / Q000235:genetics / Q000503:physiopathology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry* / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D000255:Adenosine Triphosphate; D051057:Proto-Oncogene Proteins c-akt