AKT crystal structure and__ AKT-specific inhibitors.pdfVIP

Oncogene 2005 24, 7493–7501 2005 Nature Publishing Group All rights reserved 0950-9232/05 $30.00 /onc AKT crystal structure and AKT-speci?c inhibitors Chandra C Kumar*,1 and Vincent Madison2 1Department of Tumor Biology, Schering-Plough Research Institute, 2015, Galloping Hill Road, Kenilworth, NJ 07033, USA; 2Department of Structural Chemistry, Schering-Plough Research Institute, 2015, Galloping Hill Road, Kenilworth, NJ 07033, USA AKT kinases are attractive targets for small molecule considers inhibitors of other components of the AKT drug discovery because of their key role in tumor cell pathway. survival/proliferation and their overexpression/activation in many human cancers. This review summarizes studies that support the rationale for targeting AKT kinases in Rationale for targeting AKT for new drug discovery new drug discovery efforts. Structural features of AKT kinase in its inactive and active states, as determined by AKT kinases have been selected as targets for anticancer crystal structure analysis, are described. Recent efforts in therapeutics at many academic and pharmaceutical the development and biological evaluation of small institutions based on the rationale summarized below molecule inhibitors of AKT, and the challenges remaining are summarized. Inhibitors targeting the ATP binding Reintroduction of wild-type PTEN into tumor cells that are mutant for PTEN resulted in inhibition of site, PH domain and protein substrate binding site, as well as isoform selective allosteric inhibitors are reviewed. AKT activation leading to either cell cycle arrest Structure-based design using PKA mutants as surrogates glioblastomas, renal cell carcinoma lines or apop- and computer modeling in the discovery of selective tosis breast and prostate tumor cell lines Li et al., 1998; Di Cristofano and Pa