Repurposing neurological drugs for brain cancer therapeutics: A systematic approach to identify charged molecules for...

Treatment of glioblastoma (GBM) presents significant challenges due to its high degree of heterogeneity and poor prognosis. Recurrence of the malignancy is frequent even after the standard treatment, including surgery, radiotherapy, and chemotherapy with temozolomide. Drug repurposing offers a cost-effective strategy to identify new treatments, while affinity-based local delivery systems could provide controlled release of therapeutics within the tumor resection cavity. The aims of this study are two-fold. Firstly, to categorize currently available neurological therapeutics according to their charge and suitability for use with affinity-based drug delivery systems. Secondly, to systematically search and evaluate the evidence for anticancer and/or anti-glioblastoma activity for potentially being repurposed/repositioned. The 'neurology/psychiatry' category of the Broad Institute Drug Repurposing Hub (468 compounds) was screened for chemical suitability and anticancer efficacy. Charge, lipophilicity, solubility at pH 7.4 were calculated using Chemicalize. A systematic search for the anticancer efficacy of the charged compounds was carried out via the following databases: PubMed, Scopus, Sci-Finder, Ovid via Medline, Cochrane and ClinicalTrial.gov. Among the 468 compounds, 283 were identified as charged at physiological pH. Notably, 146 charged candidates were found to have anticancer activity, of which 91 showed promising activity against at least one type of brain neoplasm. A few compounds, such as chlorpromazine, valproic acid and sertraline were investigated in clinical settings, while most were assessed through in vitro viability studies. The data complied herein should serve as a repository and starting point for future research on repurposing neurological drugs with anticancer properties via electrostatic affinity-based drug delivery systems.