Phenylalanine-Based Inactivator of AKT Kinase: Design, Synthesis, and Biological Evaluation.

ABSTRACT: Strategies to inhibit kinases by targeting the substrate binding site offer many advantages, including naturally evolved selectivity filters, but normally suffer from poor potency. In this work we propose a strategy to design and prepare covalent substrate-competitive kinase inhibitors as a method to improve potency. We have chosen AKT as the model kinase for this work. Using the AKT-GSK3β cocrystal structure and a reactive cysteine near the substrate binding site, we have identified phenylalanine (Phe) as an appropriate scaffold for the covalent inactivator portion of these inhibitors. By synthesizing compounds that incorporate cysteine-reactive electrophiles into phenylalanine and testing these compounds as AKT inhibitors, we have identified Boc-Phe-vinyl ketone as a submicromolar inacti

SUBMITTER: Nguyen T 

PROVIDER: S-EPMC4027749 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature