439912-45-5Relevant articles and documents
Phenylalanine-based inactivator of akt kinase: Design, synthesis, and biological evaluation
Nguyen, Thuy,Coover, Robert A.,Verghese, Jenson,Moran, Richard G.,Ellis, Keith C.
supporting information, p. 462 - 467 (2014/06/09)
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 inactivator of AKT. We also show that Boc-Phe-vinyl ketone (1) potently inhibits AKT1 and inhibits cell growth in HCT116 and H460 cells nearly as well as AKT inhibitors GSK690693 and MK-2206, (2) is selective for kinases that possess an activation loop cysteine such as AKT, (3) requires the vinyl ketone for inactivation, (4) has inactivation that is time-dependent, and (5) alkylates Cys310 of AKT as shown by mass spectrometry. Identification of Boc-Phe-vinyl ketone as a covalent inactivator of AKT will allow the development of peptide and small-molecule substrate-competitive covalent kinase inhibitors that incorporate additional substrate binding elements to increase selectivity and potency. This proof-of-principle study also provides a basis to apply this strategy to other kinases of the AGC and CAMK families.
Synthesis and applications of propargyl pentafluorophenyl carbonate for peptide synthesis
Bhat, Ramakrishna G,Kérourédan, Erwan,Porhiel, Emmanuel,Chandrasekaran, Srinivasan
, p. 2467 - 2469 (2007/10/03)
Propargyl pentafluorophenyl carbonate was synthesised in quantitative yield by the reaction of propargyl chloroformate and pentafluorophenol. All the N-propargyloxycarbonyl (N-Poc) amino acids were obtained in good yield. The use of Poc-OPfp in peptide synthesis has been explored.
