{"doi":"10.1021/acschembio.4c00237","title":"Targeted Degradation of Protein Kinase A via a Stapled Peptide PROTAC","abstract":"High Resolution Image Download MS PowerPoint Slide Proteolysis-targeting chimeras (PROTACs) are bifunctional molecules that bind and recruit an E3 ubiquitin ligase to a targeted protein of interest, often through the utilization of a small molecule inhibitor. To expand the possible range of kinase targets that can be degraded by PROTACs, we sought to develop a PROTAC utilizing a hydrocarbon-stapled peptide as the targeting agent to bind the surface of a target protein of interest. In this study, we describe the development of a proteolysis-targeting chimera, dubbed St apled I nhibitor P eptide - PRO TAC or StIP-TAC, linking a hydrocarbon-stapled peptide with an E3 ligase ligand for targeted degradation of Protein Kinase A (PKA). This StIP-TAC molecule stimulated E3-mediated protein degradation of PKA, and this effect could be reversed by the addition of the proteasomal inhibitor MG-132. Further, StIP-TAC treatment led to a significant reduction in PKA substrate phosphorylation. Since many protein targets of interest lack structural features that make them amenable to small molecule targeting, development of StIP-TACs may broaden the potential range of protein targets using a PROTAC-mediated proteasomal degradation approach.","journal":"ACS Chemical Biology","year":2024,"id":466157,"datarank":0.24141568686511508,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.0,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9586,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":740409,"name":"George N. Bendzunas","orcid":null,"position":1,"is_corresponding":false},{"id":1297958,"name":"Mahsa Shirani","orcid":"0009-0008-5171-3808","position":2,"is_corresponding":false},{"id":1298388,"name":"Timothy J. LeClair","orcid":null,"position":3,"is_corresponding":false},{"id":666443,"name":"Bassem Shebl","orcid":"0009-0004-8128-2536","position":4,"is_corresponding":false},{"id":1298389,"name":"Taylor C. Dill","orcid":null,"position":5,"is_corresponding":false},{"id":489209,"name":"Philip Coffino","orcid":"0000-0003-0344-5083","position":6,"is_corresponding":false},{"id":281269,"name":"Sanford M. Simon","orcid":"0000-0002-8615-4224","position":7,"is_corresponding":false},{"id":579740,"name":"Eileen J. Kennedy","orcid":"0000-0001-5610-1677","position":8,"is_corresponding":false},{"id":1297957,"name":"Matthew K. Whittaker","orcid":"0000-0002-1846-6402","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:04:54.606394Z","pmid":"39137166","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}