{"doi":"10.1101/2024.07.13.603377","title":"Small molecule FICD inhibitors suppress endogenous and pathologic FICD-mediated protein AMPylation","abstract":"Summary The AMP transferase, FICD, is an emerging drug target finetuning stress signaling in the endoplasmic reticulum (ER). FICD is a bi-functional enzyme, catalyzing both AMP addition (AMPylation) and removal (deAMPylation) from the ER resident chaperone BiP/GRP78. Despite increasing evidence linking excessive BiP/GRP78 AMPylation to human diseases, small molecules to inhibit pathogenic FICD variants are lacking. Using an in-vitro high-throughput screen, we identify two small-molecule FICD inhibitors, C22 and C73. Both molecules significantly inhibit FICD-mediated BiP/GRP78 AMPylation in intact cells while only weakly inhibiting BiP/GRP78 deAMPylation. C22 and C73 also efficiently inhibit pathogenic FICD variants and improve proinsulin processing in β cells. Our study identifies and validates FICD inhibitors, highlighting a novel therapeutic avenue against pathologic protein AMPylation.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":491405,"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":0.9523,"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":651122,"name":"Maroof Alam","orcid":"0000-0002-5085-8094","position":1,"is_corresponding":false},{"id":449224,"name":"Arghya Chakravorty","orcid":"0000-0002-4467-1135","position":2,"is_corresponding":false},{"id":370197,"name":"Shannon M. Lacy","orcid":null,"position":3,"is_corresponding":false},{"id":1337008,"name":"Jason C. Rech","orcid":"0000-0002-5876-2994","position":4,"is_corresponding":false},{"id":299321,"name":"Charles L. Brooks","orcid":"0000-0002-8149-5417","position":5,"is_corresponding":false},{"id":1337366,"name":"Peter D. Arvan","orcid":null,"position":6,"is_corresponding":false},{"id":716912,"name":"Matthias C. Truttmann","orcid":"0000-0002-0536-7923","position":7,"is_corresponding":false},{"id":716911,"name":"Bhaskar K. Chatterjee","orcid":"0000-0003-2626-5763","position":0,"is_corresponding":true}],"reference_count":56,"raw_metadata":null,"created_at":"2026-07-19T02:08:45.247225Z","pmid":"39071275","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":[]}