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We designed these inhibitors with a combinatorial chemistry approach fusing selective LRRK2 type I and promiscuous type II inhibitors using iterative cycles of synthesis supported by structural biology and activity testing. Our lead compounds are selective and potent toward both LRRK2 and LRRK1, a close relative of LRRK2. Through cellular assays, cryo\u2013electron microscopy structural analysis, and in vitro motility assays, we show that our inhibitors stabilize the open, inactive LRRK2 kinase conformation. These new conformation-specific compounds will be invaluable as tools to study LRRK2\u2019s function and regulation and expand the potential therapeutic options for PD.<\/jats:p>","DOI":"10.1126\/sciadv.adt2050","type":"journal-article","created":{"date-parts":[[2025,6,11]],"date-time":"2025-06-11T11:24:07Z","timestamp":1749641047000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":37,"title":["Type II kinase inhibitors that target Parkinson\u2019s disease\u2013associated LRRK2"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2075-7938","authenticated-orcid":true,"given":"Nicolai D.","family":"Raig","sequence":"first","affiliation":[{"name":"Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany."},{"name":"Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, 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