{"doi":"10.26434/chemrxiv.13755763","title":"Development of an Acrylamide-Based Inhibitor of Protein S-Acylation","abstract":"<p>Protein <i>S</i>-acylation is a dynamic lipid post-translational modification that can modulate the localization and activity of target proteins. In humans, the installation of the lipid onto target proteins is catalyzed by a family of 23 Asp-His-His-Cys domain-containing protein acyltransferases (DHHC-PATs). DHHCs are increasingly recognized as critical players in cellular signaling events and in human disease. However, progress elucidating the functions and mechanisms of DHHC “writers” has been hampered by a lack of chemical tools to perturb their activity in live cells. Herein, we report the synthesis and characterization of <b>cyano-myracrylamide (CMA)</b>, a broad-spectrum DHHC family inhibitor with similar potency to 2-bromopalmitate (2BP), the most commonly used DHHC inhibitor in the field. Possessing an acrylamide warhead instead of 2BP’s α-halo fatty acid, <b>CMA </b>inhibits DHHC family proteins <i>in cellulo</i> while demonstrating decreased toxicity and avoiding inhibition<b> </b>of the <i>S-</i>acylation eraser enzymes – two of the major weaknesses of 2BP. Our studies show that <b>CMA </b>engages with DHHC family proteins in cells, inhibits protein <i>S-</i>acylation, and disrupts DHHC-regulated cellular events. <b>CMA</b> represents an improved chemical scaffold for untangling the complexities of DHHC-mediated cell signaling by protein <i>S</i>-acylation.</p>","journal":"ChemRxiv","year":2021,"id":222430,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9596,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":646448,"name":"Tong Lan","orcid":"0000-0003-3923-5408","position":1,"is_corresponding":false},{"id":646449,"name":"Clémence Delalande","orcid":"0000-0001-8285-9609","position":2,"is_corresponding":false},{"id":813930,"name":"Rahul Kathayat","orcid":null,"position":3,"is_corresponding":false},{"id":813931,"name":"Fernando Benales Mejia","orcid":null,"position":4,"is_corresponding":false},{"id":656347,"name":"Alice Qin","orcid":null,"position":5,"is_corresponding":false},{"id":655790,"name":"Noah Brookes","orcid":"0000-0002-8088-0022","position":6,"is_corresponding":false},{"id":655791,"name":"Perla Sandoval","orcid":"0009-0009-9281-2084","position":7,"is_corresponding":false},{"id":551852,"name":"Bryan C. Dickinson","orcid":"0000-0002-9616-1911","position":8,"is_corresponding":false},{"id":551843,"name":"Saara‐Anne Azizi","orcid":"0000-0002-9226-9917","position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":null,"created_at":"2026-07-18T23:54:03.549854Z","pmid":null,"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":[]}