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Degradation of Akt using protein-catalyzed capture agents.

ABSTRACT: 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.

SUBMITTER: Henning RK

PROVIDER: S-EPMC4883657 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Degradation of Akt using protein-catalyzed capture agents.

Henning Ryan K RK Varghese Joseph O JO Das Samir S Nag Arundhati A Tang Grace G Tang Kevin K Sutherland Alexander M AM Heath James R JR

Journal of peptide science : an official publication of the European Peptide Society 20160216 4

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 pr ...[more]

PMID: 26880702

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