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Thus, manipulating DYRK1A activity in the brain has emerged as a potential therapeutic target for neurological disorders. Several DYRK1A inhibitors have shown promise for improving cognition in rodent models of Down syndrome and Alzheimer's disease, for example, but the ability of these inhibitors to affect DYRK1A levels or activity in relevant human cells has not been established. We filled this gap by testing the effects of a new DYRK1A inhibitor on trisomy 21 induced pluripotent stem cell (iPSC)-derived neural progenitor cells and neurons, in which DYRK1A expression and activity are increased. Our results demonstrated that Leucettinib-21, a potent and selective low-molecular-mass pharmacological inhibitor of DYRK1A, decreases DYRK1A activity in human trisomy 21 iPSC-derived neural progenitor cells and cortical neurons. Leucettinib-21 reduces DYRK1A activity in a relevant human disease model, supporting future human trials.<\/jats:p>","DOI":"10.1242\/dmm.052740","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T08:27:02Z","timestamp":1782721622000},"source":"Crossref","is-referenced-by-count":3,"title":["Leucettinib-21 decreases dosage effects of\n                    <i>DYRK1A<\/i>\n                    in human trisomy 21 induced pluripotent stem cell-derived neural cells"],"prefix":"10.1242","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0446-4294","authenticated-orcid":false,"given":"Nicole R.","family":"West","sequence":"first","affiliation":[{"name":"Waisman Center, University of Wisconsin-Madison 1 , Madison, WI ,","place":["USA"]},{"name":"University of Wisconsin-Madison 2 Cellular and Molecular Biology Graduate Program , , Madison WI 53706 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mattias F.","family":"Lindberg","sequence":"additional","affiliation":[{"name":"Perha Pharmaceuticals, Perharidy Peninsula 3 , 29680 Roscoff ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"Dairou","sequence":"additional","affiliation":[{"name":"UMR 8601 CNRS, Universit\u00e9 Paris Cit\u00e9 4 Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques , , Paris 75270 ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shawn","family":"MacGregor","sequence":"additional","affiliation":[{"name":"Waisman Center, University of Wisconsin-Madison 1 , Madison, WI ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sahith","family":"Puthireddy","sequence":"additional","affiliation":[{"name":"Waisman Center, University of Wisconsin-Madison 1 , Madison, WI ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent","family":"Meijer","sequence":"additional","affiliation":[{"name":"Perha Pharmaceuticals, Perharidy Peninsula 3 , 29680 Roscoff ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0360-7145","authenticated-orcid":false,"given":"Anita","family":"Bhattacharyya","sequence":"additional","affiliation":[{"name":"Waisman Center, University of Wisconsin-Madison 1 , Madison, WI ,","place":["USA"]},{"name":"School of Medicine and Public Health, University of Wisconsin-Madison 5 Department of Cell and Regenerative Biology , , Madison, WI 53705 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2026,6,29]]},"reference":[{"key":"2026062904265331100_DMM052740C1","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/j.pharmthera.2015.03.004","article-title":"DYRK1A in neurodegeneration and cancer: molecular basis and clinical implications","volume":"151","author":"Abbassi","year":"2015","journal-title":"Pharmacol. 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