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Published April 2016 | Accepted Version
Journal Article Open

Degradation of Akt using protein-catalyzed capture agents


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.

Additional Information

© 2016 European Peptide Society and John Wiley & Sons, Ltd. Article first published online: 16 FEB 2016. Manuscript Accepted: 30 DEC 2015. Manuscript Revised: 29 DEC 2015. Manuscript Received: 21 OCT 2015. Funded by: National Cancer Institute. Grant Number: 1U54CA199090-01 Institute for Collaborative Biotechnologies. Grant Number: W911NF-09-0001

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Accepted Version - nihms-787673.pdf


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