{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T19:29:32Z","timestamp":1778786972105,"version":"3.51.4"},"posted":{"date-parts":[[2024,9,18]]},"group-title":"Cell Biology","reference-count":55,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,9,18]],"date-time":"2024-09-18T00:00:00Z","timestamp":1726617600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,2,13]]},"abstract":"<jats:p>Aberrant increases in kinase activity of leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson\u2019s 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\u2019s function and regulation, and expand the potential therapeutic options for PD.<\/jats:p>","DOI":"10.1101\/2024.09.17.613365","type":"posted-content","created":{"date-parts":[[2024,9,18]],"date-time":"2024-09-18T12:31:20Z","timestamp":1726662680000},"source":"Crossref","is-referenced-by-count":2,"title":["Type-II kinase inhibitors that target Parkinson\u2019s Disease-associated LRRK2"],"prefix":"10.64898","author":[{"given":"Nicolai D.","family":"Raig","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katherine J.","family":"Surridge","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marta","family":"Sanz-Murillo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Verena","family":"Dederer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Kr\u00e4mer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1252-1829","authenticated-orcid":false,"given":"Martin P.","family":"Schwalm","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lewis","family":"Elson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deep","family":"Chatterjee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sebastian","family":"Mathea","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7202-9468","authenticated-orcid":false,"given":"Thomas","family":"Hanke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andres E.","family":"Leschziner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1553-465X","authenticated-orcid":false,"given":"Samara L.","family":"Reck-Peterson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Knapp","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025021505551052000_2024.09.17.613365v3.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41531-022-00410-y"},{"key":"2025021505551052000_2024.09.17.613365v3.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2004.10.023"},{"key":"2025021505551052000_2024.09.17.613365v3.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2004.11.005"},{"key":"2025021505551052000_2024.09.17.613365v3.4","doi-asserted-by":"publisher","DOI":"10.1038\/ng.485"},{"key":"2025021505551052000_2024.09.17.613365v3.5","doi-asserted-by":"publisher","DOI":"10.1038\/ng.487"},{"key":"2025021505551052000_2024.09.17.613365v3.6","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aar5429"},{"key":"2025021505551052000_2024.09.17.613365v3.7","first-page":"412","article-title":"A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson\u2019s disease","volume":"365","year":"2005","journal-title":"The Lancet"},{"key":"2025021505551052000_2024.09.17.613365v3.8","first-page":"410","article-title":"Genetic screening for a single common LRRK2 mutation in familial Parkinson\u2019s disease","volume":"365","year":"2005","journal-title":"The Lancet"},{"key":"2025021505551052000_2024.09.17.613365v3.9","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(05)17830-1"},{"key":"2025021505551052000_2024.09.17.613365v3.10","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0507360102"},{"key":"2025021505551052000_2024.09.17.613365v3.11","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c00963"},{"key":"2025021505551052000_2024.09.17.613365v3.12","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.538"},{"key":"2025021505551052000_2024.09.17.613365v3.13","doi-asserted-by":"publisher","DOI":"10.1021\/cb2002413"},{"key":"2025021505551052000_2024.09.17.613365v3.14","doi-asserted-by":"publisher","DOI":"10.1021\/jm301020q"},{"key":"2025021505551052000_2024.09.17.613365v3.15","doi-asserted-by":"publisher","DOI":"10.1021\/jm5014055"},{"key":"2025021505551052000_2024.09.17.613365v3.16","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.115.227587"},{"key":"2025021505551052000_2024.09.17.613365v3.17","doi-asserted-by":"publisher","DOI":"10.1101\/2021.05.21.445132"},{"key":"2025021505551052000_2024.09.17.613365v3.18","doi-asserted-by":"crossref","unstructured":"M. S. Murillo , A. V. Suarez , V. Dederer , D. Chatterjee , J. A. Louro , S. Knapp , S. Mathea , A. E. Leschziner , Inhibition of Parkinson\u2019s disease\u2013 related LRRK2 by type I and type II kinase inhibitors: Activity and structures. SCIENCE ADVANCES (2023).","DOI":"10.1101\/2023.09.07.556689"},{"key":"2025021505551052000_2024.09.17.613365v3.19","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2673-2"},{"key":"2025021505551052000_2024.09.17.613365v3.20","doi-asserted-by":"publisher","DOI":"10.1021\/cb500129t"},{"key":"2025021505551052000_2024.09.17.613365v3.21","doi-asserted-by":"publisher","DOI":"10.1021\/jm501603h"},{"key":"2025021505551052000_2024.09.17.613365v3.22","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/s41421-023-00639-8","article-title":"Pharmacology of LRRK2 with type I and II kinase inhibitors revealed by cryo-EM","volume":"10","year":"2024","journal-title":"Cell Discov"},{"key":"2025021505551052000_2024.09.17.613365v3.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.08.004"},{"key":"2025021505551052000_2024.09.17.613365v3.24","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2100844118"},{"key":"2025021505551052000_2024.09.17.613365v3.25","doi-asserted-by":"publisher","DOI":"10.1038\/s41594-022-00863-y"},{"key":"2025021505551052000_2024.09.17.613365v3.26","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddx410"},{"key":"2025021505551052000_2024.09.17.613365v3.27","doi-asserted-by":"publisher","DOI":"10.1021\/bi100157u"},{"key":"2025021505551052000_2024.09.17.613365v3.28","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abb2454"},{"key":"2025021505551052000_2024.09.17.613365v3.29","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi439"},{"key":"2025021505551052000_2024.09.17.613365v3.30","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddr526"},{"key":"2025021505551052000_2024.09.17.613365v3.31","doi-asserted-by":"publisher","DOI":"10.1042\/BCJ20210375"},{"key":"2025021505551052000_2024.09.17.613365v3.32","doi-asserted-by":"crossref","unstructured":"R. N. Fuji , M. Flagella , M. Baca , M. A. S. Baptista , J. Brodbeck , B. K. Chan , B. K. Fiske , L. Honigberg , A. M. Jubb , P. Katavolos , D. W. Lee , S.-C. Lewin-Koh , T. Lin , X. Liu , S. Liu , J. P. Lyssikatos , J. O\u2019Mahony , M. Reichelt , M. Roose-Girma , Z. Sheng , T. Sherer , A. Smith , M. Solon , Z. K. Sweeney , J. Tarrant , A. Urkowitz , S. Warming , M. Yaylaoglu , S. Zhang , H. Zhu , A. A. Estrada , R. J. Watts , Effect of selective LRRK2 kinase inhibition on nonhuman primate lung. Sci. Transl. Med. 7 (2015).","DOI":"10.1126\/scitranslmed.aaa3634"},{"key":"2025021505551052000_2024.09.17.613365v3.33","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0080705"},{"key":"2025021505551052000_2024.09.17.613365v3.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2024.107469"},{"key":"2025021505551052000_2024.09.17.613365v3.35","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-011420-092302"},{"key":"2025021505551052000_2024.09.17.613365v3.36","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.12813"},{"key":"2025021505551052000_2024.09.17.613365v3.37","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.1938"},{"key":"2025021505551052000_2024.09.17.613365v3.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.04.032"},{"key":"2025021505551052000_2024.09.17.613365v3.39","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2007.321"},{"key":"2025021505551052000_2024.09.17.613365v3.40","doi-asserted-by":"publisher","DOI":"10.3390\/ijms232314834"},{"key":"2025021505551052000_2024.09.17.613365v3.41","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444909047337"},{"key":"2025021505551052000_2024.09.17.613365v3.42","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444913000061"},{"key":"2025021505551052000_2024.09.17.613365v3.43","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.0c00898"},{"key":"2025021505551052000_2024.09.17.613365v3.44","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444907049839"},{"key":"2025021505551052000_2024.09.17.613365v3.45","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444904019158"},{"key":"2025021505551052000_2024.09.17.613365v3.46","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444904023510"},{"key":"2025021505551052000_2024.09.17.613365v3.47","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4169"},{"key":"2025021505551052000_2024.09.17.613365v3.48","doi-asserted-by":"publisher","DOI":"10.1017\/s143192761900566x"},{"key":"2025021505551052000_2024.09.17.613365v3.49","doi-asserted-by":"publisher","DOI":"10.1002\/PRO.3943"},{"key":"2025021505551052000_2024.09.17.613365v3.50","doi-asserted-by":"publisher","DOI":"10.1038\/S41592-022-01488-1"},{"key":"2025021505551052000_2024.09.17.613365v3.51","doi-asserted-by":"publisher","DOI":"10.1107\/S2059798319011471"},{"key":"2025021505551052000_2024.09.17.613365v3.52","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444910007493"},{"key":"2025021505551052000_2024.09.17.613365v3.53","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-024-00979-z"},{"key":"2025021505551052000_2024.09.17.613365v3.54","doi-asserted-by":"publisher","DOI":"10.21203\/rs.3.rs-3967452\/v1"},{"key":"2025021505551052000_2024.09.17.613365v3.55","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.02641"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.09.17.613365","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T07:03:53Z","timestamp":1768460633000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2024.09.17.613365"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,18]]},"references-count":55,"URL":"https:\/\/doi.org\/10.1101\/2024.09.17.613365","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1126\/sciadv.adt2050","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2024,9,18]]},"subtype":"preprint"}}