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

Research output: Contribution to journalArticle

Authors

  • Chiara Greco
  • Vincenzo Taresco
  • Catherine E. Vasey
  • Stuart Smith
  • Ruman Rahman
  • Cameron Alexander
  • Robert J. Cavanagh
  • Francesca Musumeci
  • Silvia Schenone

Colleges, School and Institutes

External organisations

  • University of Genoa
  • University of Nottingham

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.

Details

Original languageEnglish
JournalACS Medicinal Chemistry Letters
Publication statusAccepted/In press - 1 Jan 2020

Keywords

  • glioblastoma multiforme, inkjet 2D printing, invasive margin cells, Kinase inhibitors, miniaturized assay