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

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

doi:10.1021/acsmedchemlett.9b00530

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

ACS Med Chem Lett. 2020 Feb 13;11(5):657-663. doi: 10.1021/acsmedchemlett.9b00530. eCollection 2020 May 14.

Authors

Affiliations

¹ Department of Pharmacy, University of Genoa, Viale Benedetto XV 3, 16132 Genoa, Italy.
² School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, U.K.
³ School of Chemistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K.
⁴ School of Pharmacy, University of Nottingham, University Park, Nottingham NG7 2RD, U.K.
⁵ Children's Brain Tumour Research Centre, School of Medicine, University of Nottingham, Nottingham NG7 2UH, U.K.

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.