Invited Speaker 7th Modern Solid Phase Peptide Synthesis & Its Applications Symposium 2019

Harnessing oxidative post-translational modifications: a new strategy for precision medicine development  (#39)

Xuyu Liu 1
  1. The University of Sydney, The Heart Research Institute, Lausanne, VAUD, Switzerland

Post-translational modifications (PTMs) afford proteins new functions to reshape their interactomes and orchestrate complex cellular responses to environmental cues or signaling molecules. Oxidative PTMs of proteins by lipid-electrophiles have been implicated in pathogenesis of tumors through modulation of signaling pathways controlling cell growth, division and apoptosis1-3. However, conventional genetic/biochemical means, such as si/shRNA knockdown and site-directed mutagenesis, are not suited to study protein-PTM interactions in a spatiotemporally controlled manner. Therefore, we developed a genome-wide chemoproteomic platform to enable precision tracking of lipid-electrophile PTMs in living systems1, 4-5. This platform engendered the discovery of an isozyme-specific cysteine hydroxynonenylation occurring on Akt3 oncogenic kinase, which ultimately initiates apoptosis in cells. In this talk, I will focus on the development of Akt3 isozyme-specific covalent inhibitors through hijacking this innate oxidative PTM. The pharmacological advantages of such compounds in vivo will be compared to conventional pan-Akt kinase inhibitors in clinical trials. Our findings further promise a novel gateway to the design and development of isozyme-specific covalent ligands derived from understanding precise oxidative PTMs at the molecular level. 

  1. Liu, X.; Long, M. J. C.; Aye, Y., "Proteomics and Beyond: Cell Decision-Making Shaped by Reactive Electrophiles". Trends in Biochemical Sciences 2019, 44 (1), 75-89.
  2. Long, M. J. C.; Liu, X.; Aye, Y., "Genie in a bottle: controlled release helps tame natural polypharmacology?". Current Opinion in Chemical Biology 2019, 51, 48-56.
  3. Long, M. J. C.; Liu, X.; Aye, Y., "Chemical Biology Gateways to Mapping Location, Association, and Pathway Responsivity". Frontiers in Chemistry 2019, 7 (125), accepted.
  4. Long, M. J. C.; Parvez, S.; Zhao, Y., et al., "Akt3 is a privileged first responder in isozyme-specific electrophile response". Nature Chemical Biology 2017, 13, 333.
  5. Liu, X.; Long, M. J. C.; Aye, Y., PCT Patent 7879-01-US 2018.