Development of Pyrazolo[3,4-d]pyrimidine Kinase Inhibitors as Potential Clinical Candidates for Glioblastoma Multiforme
Chiara Greco1, Vincenzo Taresco2, Amanda K Pearce3
1Department of Pharmacy, University of Genoa, Viale Benedetto XV 3, 16132 Genoa, Italy.
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.
Insights
Researchers identified SI306, a Src kinase inhibitor, to target invasive glioblastoma multiforme (GBM) cells. A formulation study using inkjet printing explored oral GBM treatment options.
Area of Science:
- Oncology
- Pharmacology
- Medicinal Chemistry
Background:
- Glioblastoma multiforme (GBM) is an aggressive brain tumor with high recurrence rates.
- Residual invasive cells at the tumor margin are a primary cause of GBM recurrence.
- Targeting these invasive cells is crucial for improving GBM treatment outcomes.
Purpose of the Study:
- To identify novel compounds effective against invasive glioblastoma cells.
- To evaluate pyrazolo[3,4-d]pyrimidine derivatives as kinase inhibitors for GBM.
- To develop a feasible oral formulation for potential GBM therapy.
Main Methods:
- Screening of three pyrazolo[3,4-d]pyrimidine kinase inhibitors (targeting Src, Fyn, SGK1) against patient-derived GBM cell lines.
- Utilizing cell lines from both invasive regions and contrast-enhanced cores of GBM.
- Employing 2D inkjet printing for polymer-drug dispersion formulation.
Main Results:
- The Src inhibitor, SI306, demonstrated significant potential in eradicating invasive GBM cells.
- Successful development of soluble polymer-drug dispersions for potential oral administration.
- Identification of a class of polymer-formulated pyrazolo[3,4-d]pyrimidine kinase inhibitors.
Conclusions:
- SI306 is a promising lead compound for targeting invasive GBM.
- Polymer-formulated pyrazolo[3,4-d]pyrimidine kinase inhibitors show potential for preclinical GBM studies.
- The developed formulation approach supports the development of oral GBM treatments.
