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Genetic and pharmacological evidence suggests that the nuclear scaffolding protein WD-repeat containing protein 5 (WDR5) is a therapeutic vulnerability of the CSC population. However, previously reported WDR5 inhibitors display low permeability and are unable to penetrate the blood-brain barrier (BBB), limiting their utility in GBM. Herein, we report the structure-guided development of a series of triazole-based WDR5 WIN-site inhibitors designed to increase passive brain penetration. We identified triazole-based WDR5 inhibitors that are potent, passively permeable, and in some cases more brain penetrant than other scaffolds. We phenotypically assessed our WDR5 inhibitors in a panel of patient-derived CSC models and uncovered unique WDR5-regulated metabolic genes in GBM. We also evaluated their antiproliferative activity against CSCs both in vitro and in vivo. Finally, to identify potential combination opportunities, we screened a 2,100-compound chemical probe library and identified that the ATAD2 inhibitor BAY-850 synergizes with WDR5 inhibitors to enhance CSC killing. Our work diversifies the chemical matter targeting WDR5, clarifies the in vitro consequences of WIN-site inhibition in CSCs, and encourages the future development of next-generation WDR5 inhibitors with the potential to achieve in vivo efficacy in the brain.<\/jats:p>","DOI":"10.1172\/jci.insight.198298","type":"journal-article","created":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T16:01:16Z","timestamp":1777996876000},"source":"Crossref","is-referenced-by-count":0,"title":["Development and characterization of triazole-based WDR5 inhibitors for the treatment of glioblastoma"],"prefix":"10.1172","volume":"11","author":[{"given":"Jesse A.","family":"Coker","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA."},{"name":"Cleveland Clinic Center for Therapeutics Discovery (C3TD), Cleveland Clinic Research, Cleveland, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven R.","family":"Martinez","sequence":"additional","affiliation":[{"name":"Cleveland Clinic Center for Therapeutics Discovery (C3TD), Cleveland Clinic Research, Cleveland, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang Hoon","family":"Han","sequence":"additional","affiliation":[{"name":"Cleveland Clinic Center for Therapeutics Discovery (C3TD), Cleveland Clinic Research, Cleveland, Ohio, USA."},{"name":"College of Pharmacy, Korea University, Sejong, Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony R.","family":"Sloan","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Cleveland Clinic Research, Cleveland, Ohio, USA."},{"name":"Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit Kumar","family":"Gupta","sequence":"additional","affiliation":[{"name":"Cleveland Clinic Genome Center and"},{"name":"Genomic Medicine Institute, Cleveland Clinic Research, Cleveland, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Bukenya","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Cleveland Clinic Research, Cleveland, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Polzer","sequence":"additional","affiliation":[{"name":"Cleveland Clinic Center for Therapeutics Discovery (C3TD), Cleveland Clinic Research, Cleveland, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James H.","family":"Ramos","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Cleveland Clinic Research, Cleveland, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma G.","family":"Rico","sequence":"additional","affiliation":[{"name":"Cleveland Clinic Center for Therapeutics Discovery (C3TD), Cleveland Clinic Research, Cleveland, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annabella","family":"Rico","sequence":"additional","affiliation":[{"name":"Cleveland Clinic Center for Therapeutics Discovery (C3TD), Cleveland Clinic Research, Cleveland, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. 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