Sunitinib-Containing Carborane Pharmacophore with the Ability to Inhibit Tyrosine Kinases Receptors FLT3, KIT and PDGFR-β, Exhibits Powerful In Vivo Anti-Glioblastoma Activity.

Simple Summary Glioblastoma is one of the most aggressive central nervous system tumors. Combinations of therapies, such as tyrosine kinase receptor inhibition and boron neutron capture therapy (BNCT), could offer greater patients benefits over single-therapies. The aim of our study was to assess the potential of sunitinib-carborane hybrid compound 1 as an anti-glioblastoma agent. We confirmed for 1 the ability to inhibit tyrosine kinase receptors, which could promote canonical and non-canonical effects, absence of mutagenicity, ability to cross the blood-brain barrier, and powerful in vivo anti-glioblastoma activity. The overall attractive profile of 1 makes it an interesting compound for a bimodal therapeutic strategy against high grade gliomas. Malignant gliomas are the most common malignant and aggressive primary brain tumors in adults, the prognosis being-especially for glioblastomas-extremely poor. There are no effective treatments yet. However, tyrosine kinase receptor (TKR) inhibitors and boron neutron capture therapy (BNCT), together, have been proposed as future therapeutic strategies. In this sense in our ongoing project of developing new anti-glioblastoma drugs, we identified a sunitinib-carborane hybrid agent, 1, with both in vitro selective cytotoxicity and excellent BNCT-behavior. Consequently, we studied the ability of compound 1 to inhibit TKRs, its promotion of cellular death processes, and its effects on the cell cycle. Moreover, we analyzed some relevant drug-like properties of 1, i.e., mutagenicity and ability to cross the blood-brain barrier. These results encouraged us to perform an in vivo anti-glioblastoma proof of concept assay. It turned out to be a selective FLT3, KIT, and PDGFR-beta inhibitor and increased the apoptotic glioma-cell numbers and arrested sub-G1-phase cell cycle. Its in vivo activity in immunosuppressed mice bearing U87 MG human glioblastoma evidenced excellent anti-tumor behavior.