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.
Highlights
Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor
Problems with existing treatment approaches include (i) increased resistance to chemotherapeutic drugs caused by the heterogeneity of the tumor microenvironment and variation in tumor subclones, (ii) inability or impairment of drugs to cross the blood−brain barrier (BBB), and (iii) lack of penetration of locally delivered therapeutic agents deep into the brain parenchyma beyond the resection cavity at sufficient therapeutic concentrations to target residual tumor cells.[3,4]
GBM recurrence, which is inevitable with current treatment methods
Summary
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. Our group has designed and synthesized a wide library of pyrazolo[3,4-d]pyrimidines active as kinase inhibitors.[27,28] In particular, three of our in-house compounds (SI306, SI308, and SI113 (Figure 1)) have been shown to be potent inhibitors of the tyrosine kinases Src and Fyn and serine-threonine kinase SGK1,29−31 respectively, and have demonstrated anticancer effects on different commercial (established) GBM cell lines.[30,32,33]
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