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DYRK1A drives glioblastoma (GBM) progression via stabilization of epidermal growth factor receptor (EGFR). Here we describe two, selective, benzothiazole-derived DYRK inhibitors, FC-2 and FC-3, obtained by structure\u2013activity optimization of a natural product lead. Both compounds inhibit DYRK1A with nanomolar potency and display high selectivity across a kinase panel. The co-crystal structure of FC-3 with DYRK1A revealed ATP-competitive binding, with interactions at the hinge region and the DYRK-specific phenylalanine gatekeeper residue explaining target selectivity. Generation of inhibitor-resistant mutants confirmed DYRK1A as the primary cellular target. In GBM cell-models, FC-2 and FC-3 impaired neurosphere self-renewal, cell invasion, and EGFR stability, phenocopying DYRK1A loss. Both compounds crossed the blood\u2013brain barrier and suppressed tumor growth, to prolong survival in intracranial xenografts. These findings identify FC-2 and FC-3 as selective small-molecule inhibitors of DYRK1A with potential therapeutic utility in GBM.<\/jats:p>","DOI":"10.1101\/2025.11.05.686653","type":"posted-content","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T23:45:14Z","timestamp":1762472714000},"source":"Crossref","is-referenced-by-count":0,"title":["Novel small-molecule inhibitors of the protein kinase DYRK: Potential therapeutic candidates in cancer"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9106-0102","authenticated-orcid":false,"given":"Prabhadevi","family":"Venkataramani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elad","family":"Elkayam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ankur","family":"Garg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai Fan","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad","family":"Altiti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingzhu","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khushabu","family":"Thakur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evdokia","family":"Michalopoulou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camila","family":"Gonzalez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christy","family":"Felice","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Van-Aelst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darryl","family":"Pappin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leemor","family":"Joshua-Tor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yousef","family":"Al-Abed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas K.","family":"Tonks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025111016450535000_2025.11.05.686653v2.1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-4658.2010.07956.x"},{"key":"2025111016450535000_2025.11.05.686653v2.2","doi-asserted-by":"crossref","first-page":"R488","DOI":"10.1016\/j.cub.2015.02.067","article-title":"DYRK protein kinases","volume":"25","year":"2015","journal-title":"Curr. 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