Development of Pyrazolo[3,4- d]pyrimidine Kinase Inhibitors as Potential Clinical Candidates for Glioblastoma Multiforme

Greco, Chiara; Taresco, Vincenzo; Pearce, Amanda K.; Vasey, Catherine E.; Smith, Stuart; Rahman, Ruman; Alexander, Cameron; Cavanagh, Robert J.; Musumeci, Francesca; Schenone, Silvia

Abstract

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.

Citation

Greco, C., Taresco, V., Pearce, A. K., Vasey, C. E., Smith, S., Rahman, R., Alexander, C., Cavanagh, R. J., Musumeci, F., & Schenone, S. (2020). Development of Pyrazolo[3,4- d]pyrimidine Kinase Inhibitors as Potential Clinical Candidates for Glioblastoma Multiforme. ACS Medicinal Chemistry Letters, 11(5), 657-663. https://doi.org/10.1021/acsmedchemlett.9b00530

• Journal Article Type: Article
• Acceptance Date: Feb 13, 2020
• Online Publication Date: Feb 19, 2020
• Publication Date: May 14, 2020
• Deposit Date: Mar 4, 2022
• Publicly Available Date: Mar 7, 2022
• Journal: ACS Medicinal Chemistry Letters
• Electronic ISSN: 1948-5875
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 11
• Issue: 5
• Pages: 657-663
• DOI: https://doi.org/10.1021/acsmedchemlett.9b00530
• Public URL: https://nottingham-repository.worktribe.com/output/4007035
• Publisher URL: https://pubs.acs.org/doi/10.1021/acsmedchemlett.9b00530