{"doi":"10.1101/2024.09.17.613365","title":"Type-II kinase inhibitors that target Parkinson’s Disease-associated LRRK2","abstract":"Aberrant increases in kinase activity of leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson's disease (PD). Numerous LRRK2-selective type-I kinase inhibitors have been developed and some have entered clinical trials. In this study, we present the first LRRK2-selective type-II kinase inhibitors. Targeting the inactive conformation of LRRK2 is functionally distinct from targeting the active-like conformation using type-I inhibitors. We designed these inhibitors using a combinatorial chemistry approach fusing selective LRRK2 type-I and promiscuous type-II inhibitors by iterative cycles of synthesis supported by structural biology and activity testing. Our current lead structures are selective and potent LRRK2 inhibitors. Through cellular assays, cryo-electron microscopy structural analysis, and in vitro motility assays, we show that our inhibitors stabilize the open, inactive kinase conformation. These new conformation-specific compounds will be invaluable as tools to study LRRK2's function and regulation, and expand the potential therapeutic options for PD.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":486352,"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":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9552,"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":1329761,"name":"Katherine J. Surridge","orcid":"0000-0003-0048-5784","position":1,"is_corresponding":false},{"id":1031914,"name":"Marta Sanz Murillo","orcid":"0000-0002-6175-9315","position":2,"is_corresponding":false},{"id":1329762,"name":"Verena Dederer","orcid":"0000-0002-7877-4706","position":3,"is_corresponding":false},{"id":634299,"name":"Andreas Krämer","orcid":"0000-0003-3294-2660","position":4,"is_corresponding":false},{"id":817299,"name":"Martin P. Schwalm","orcid":"0000-0002-1252-1829","position":5,"is_corresponding":false},{"id":1238474,"name":"Lewis Elson","orcid":"0009-0004-6142-3653","position":6,"is_corresponding":false},{"id":279241,"name":"Deep Chatterjee","orcid":"0000-0001-8190-9213","position":7,"is_corresponding":false},{"id":239980,"name":"Sebastian Mathea","orcid":"0000-0001-8500-4569","position":8,"is_corresponding":false},{"id":877266,"name":"Thomas Hanke","orcid":"0000-0001-7202-9468","position":9,"is_corresponding":false},{"id":239990,"name":"Andrés E. Leschziner","orcid":"0000-0002-7732-7023","position":10,"is_corresponding":false},{"id":239989,"name":"Samara L. Reck‐Peterson","orcid":"0000-0002-1553-465X","position":11,"is_corresponding":false},{"id":239988,"name":"Stefan Knapp","orcid":"0000-0001-5995-6494","position":12,"is_corresponding":false},{"id":1329760,"name":"Nicolai D. Raig","orcid":"0000-0002-2075-7938","position":0,"is_corresponding":true}],"reference_count":55,"raw_metadata":null,"created_at":"2026-07-19T02:07:57.049469Z","pmid":"39554022","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":[]}