Development of Pyrazolo[3,4- d]pyrimidine Kinase Inhibitors as Potential Clinical Candidates for Glioblastoma Multiforme
| Autor: | Silvia Schenone, Robert Cavanagh, Amanda K. Pearce, Vincenzo Taresco, Francesca Musumeci, Stuart Smith, Catherine E. Vasey, Cameron Alexander, Chiara Greco, Ruman Rahman |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Cell
Population Brain tumor 01 natural sciences Biochemistry glioblastoma multiforme FYN invasive margin cells miniaturized assay Drug Discovery inkjet 2D printing medicine education Kinase inhibitors education.field_of_study urogenital system 010405 organic chemistry Kinase business.industry Organic Chemistry medicine.disease nervous system diseases 0104 chemical sciences 010404 medicinal & biomolecular chemistry medicine.anatomical_structure Cell culture Cancer research SGK1 business Proto-oncogene tyrosine-protein kinase Src |
| ISSN: | 1948-5875 |
| Popis: | Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor. Residual cells at the tumor margin are responsible for up to 85% of GBM recurrences after standard treatment. Despite this evidence, the identification of compounds active on this cell population is still an underexplored field. Herein, starting from the knowledge that kinases are implicated in GBM, we evaluated three in-house pyrazolo[3,4-d]pyrimidines active as Src, Fyn, and SGK1 kinase inhibitors against patient derived cell lines from either the invasive region or contrast-enhanced core of GBM. We identified our Src inhibitor, SI306, as a promising lead compound for eradicating invasive GBM cells. Furthermore, aiming at the development of a feasible oral treatment for GBM, we performed a formulation study using 2D inkjet printing to generate soluble polymer-drug dispersions. Overall, this study led to the identification of a set of polymer-formulated pyrazolo[3,4-d]pyrimidine kinase inhibitors as promising candidates for GBM preclinical efficacy studies. |
| Databáze: | OpenAIRE |
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