title: 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.
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, MC 127-72, Pasadena, CA 91125.
authors.forename: Ryan K
authors.initials: RK
authors.lastname: Henning
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, MC 127-72, Pasadena, CA 91125.
authors.forename: Joseph O
authors.initials: JO
authors.lastname: Varghese
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, MC 127-72, Pasadena, CA 91125.
authors.forename: Samir
authors.initials: S
authors.lastname: Das
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, MC 127-72, Pasadena, CA 91125.
authors.forename: Arundhati
authors.initials: A
authors.lastname: Nag
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, MC 127-72, Pasadena, CA 91125.
authors.forename: Grace
authors.initials: G
authors.lastname: Tang
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, MC 127-72, Pasadena, CA 91125.
authors.forename: Kevin
authors.initials: K
authors.lastname: Tang
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, MC 127-72, Pasadena, CA 91125.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Sutherland
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, MC 127-72, Pasadena, CA 91125.
authors.forename: James R
authors.initials: JR
authors.lastname: Heath
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002384:Catalysis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D020128:Inhibitory Concentration 50; D058990:Molecular Targeted Therapy; D010455:Peptides / Q000494:pharmacology*; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010455:Peptides; C000613077:tri-a triligand; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt; PROTAC; click chemistry; protein-catalyzed capture agents