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We designed and tested over 100 new compounds based on the chemical structure of fenofibrate (FF), which in its prodrug form is cytotoxic to cancer cells by causing severe impairment of mitochondrial respiration. The compounds were designed using two key predictive tools: central nervous system\u2013multiparameter optimization (CNS\u2010MPO) and BBB_SCORE. These algorithms assess how effectively compounds can penetrate the BBB. We initially selected PP1 as a lead compound by testing its BBB penetration, metabolic performance, and antitumoral efficacy. PP1 accumulated in brain tumors and triggered glioblastoma cell death. However, PP1\u2010induced inhibition of mitochondrial respiration was followed by an immediate glycolytic response, which attenuated PP1 toxicity in a glucose\u2010dependent manner. To bypass this limitation, we tested two strategies: (1) the use of PP1 in combination with glycolysis inhibitors; and (2) introduction of a new compound, PP211, which inhibited mitochondrial respiration in the absence of a concomitant increase of glycolysis. Although the combination of PP1 with glycolysis inhibitors was very effective in vitro, this drug combination demonstrated elevated toxicity in mice. PP211, instead, attenuated TMZ\u2010resistant tumor growth and prolonged mouse survival with only minimal general animal toxicity. In summary, we developed and tested a novel mitochondria\u2010targeting drug candidate, PP211, which effectively crosses the BBB, overcomes TMZ resistance, and induces tumor cell death independently of glucose levels\u2014while exhibiting minimal systemic toxicity in preclinical models. These findings support further development of PP211 for glioblastoma therapy.<\/jats:p>","DOI":"10.1002\/jcp.70062","type":"journal-article","created":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T02:24:52Z","timestamp":1752719092000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Bypassing Blood\u2010Brain Barrier and Glucose Dependency of Anti\u2010Glioblastoma Drug Candidates Targeting Mitochondrial Respiration"],"prefix":"10.1002","volume":"240","author":[{"suffix":"IV","given":"Charles H.","family":"Ingraham","sequence":"first","affiliation":[{"name":"Department of Interdisciplinary Oncology LSU Health Sciences Center New Orleans Louisiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana Polania","family":"Villanueva","sequence":"additional","affiliation":[{"name":"Department of Interdisciplinary Oncology LSU Health Sciences Center New Orleans Louisiana 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