Degradation of Akt using protein-catalyzed capture agents

J Pept Sci. 2016 Apr;22(4):196-200. doi: 10.1002/psc.2858. Epub 2016 Feb 16.


Abnormal signaling of the protein kinase Akt has been shown to contribute to human diseases such as diabetes and cancer, but Akt has proven to be a challenging target for drugging. Using iterative in situ click chemistry, we recently developed multiple protein-catalyzed capture (PCC) agents that allosterically modulate Akt enzymatic activity in a protein-based assay. Here, we utilize similar PCCs to exploit endogenous protein degradation pathways. We use the modularity of the anti-Akt PCCs to prepare proteolysis targeting chimeric molecules that are shown to promote the rapid degradation of Akt in live cancer cells. These novel proteolysis targeting chimeric molecules demonstrate that the epitope targeting selectivity of PCCs can be coupled with non-traditional drugging moieties to inhibit challenging targets.

Keywords: Akt; PROTAC; click chemistry; protein-catalyzed capture agents.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Catalysis
  • Cell Line, Tumor
  • Cell Proliferation
  • Drug Screening Assays, Antitumor
  • Enzyme Activation
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Inhibitory Concentration 50
  • Molecular Targeted Therapy
  • Peptides / pharmacology*
  • Proteolysis
  • Proto-Oncogene Proteins c-akt / metabolism*


  • Antineoplastic Agents
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Peptides
  • tri-a triligand
  • Proto-Oncogene Proteins c-akt