{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T21:40:03Z","timestamp":1770068403074,"version":"3.49.0"},"reference-count":34,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T00:00:00Z","timestamp":1765756800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R01CA281977"],"award-info":[{"award-number":["R01CA281977"]}]},{"name":"NIH","award":["R01CA148706"],"award-info":[{"award-number":["R01CA148706"]}]},{"name":"NIH","award":["R01CA276152"],"award-info":[{"award-number":["R01CA276152"]}]},{"DOI":"10.13039\/100030820","name":"University of Tennessee College of Pharmacy Drug Discovery Center","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100030820","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Glioblastoma (GBM) is an aggressive and treatment-resistant brain tumor with few effective therapies. Tubulin polymers are crucial for maintaining cell\u2013cell signaling, cell proliferation, and cell division. Therefore, tubulin has been targeted by medicinal chemists to develop novel therapeutics to treat cancer. In this regard, we developed novel small-molecule tubulin inhibitors as potential therapeutics to treat GBM. Methods: We synthesized a focused library of pyrimidine-containing dihydroquinoxalinone-based analogs and tested nine compounds for cytotoxicity in GBM cell lines using the Sulforhodamine B (SRB) cell viability assay. We identified compound 8c as the most promising compound and evaluated the in vitro effects of 8c on GBM cell growth using live cell imaging and assessed apoptosis using a cell death ELISA. We then tested its anticancer activity in vivo on GBM xenografts grown in immunocompromised mice. Results: Several compounds demonstrated nanomolar IC50 values in cell viability assays and outperformed temozolomide (TMZ), the current standard treatment for GBM patients. We identified compound 8c, which is a pyrimidine analog with a secondary amine, as the lead candidate for GBM studies in vitro and in vivo. Compound 8c reduced cell viability in a dose-dependent manner and induced complete growth arrest within 48 h at 3\u201310 nM concentrations in GBM cell lines. ELISA confirmed that compound 8c triggered dose-dependent apoptosis, whereas TMZ failed to induce apoptosis at nM concentrations. In vivo, compound 8c significantly inhibited GBM xenograft growth in immunocompromised mice by 66%. Conclusions: The potent tubulin inhibitor compound 8c has strong anti-GBM activity in vitro and in vivo and merits further preclinical development.<\/jats:p>","DOI":"10.3390\/ph18121891","type":"journal-article","created":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T10:11:23Z","timestamp":1765793483000},"page":"1891","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Pyrimidine-Based Tubulin Inhibitor Shows Potent Anti-Glioblastoma Activity In Vitro and In Vivo"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7617-9906","authenticated-orcid":false,"given":"Satyanarayana","family":"Pochampally","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2809-1234","authenticated-orcid":false,"given":"Lawrence M.","family":"Pfeffer","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Center for Cancer Research, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gustavo A.","family":"Miranda-Carboni","sequence":"additional","affiliation":[{"name":"Department of Medicine, Center for Cancer Research, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Macey","family":"Daniel","sequence":"additional","affiliation":[{"name":"Department of Medicine, Center for Cancer Research, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jazz I.","family":"James","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Center for Cancer Research, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Allana","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Center for Cancer Research, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chuan He","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Center for Cancer Research, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6825-2170","authenticated-orcid":false,"given":"Hannah R.","family":"Kelso","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Center for Cancer Research, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5125-683X","authenticated-orcid":false,"given":"Deanna N.","family":"Parke","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Center for Cancer Research, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0055-1916","authenticated-orcid":false,"given":"Dong-Jin","family":"Hwang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9522-4474","authenticated-orcid":false,"given":"Wei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6093-0985","authenticated-orcid":false,"given":"Duane D.","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1056\/NEJMoa043330","article-title":"Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma","volume":"352","author":"Stupp","year":"2005","journal-title":"N. 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