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

Catalina Alamón,Martín Gabay,Belén Dávila,Moshe Gavish,Emiliano Trias,Carina Sánchez,Nidal Zeineh,Hugo Cerecetto,Mariángeles Kovacs,Francesc Teixidor,Luis Barbeito,Clara Viñas,Marcos Couto,María Fernanda García

doi:10.3390/cancers12113423

Abstract

Simple SummaryGlioblastoma 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-β 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.

Highlights

Even though glioblastoma is one of the most frequent and aggressive adult primary central nervous system tumors, with no more than two years of survival in a low percentage (3–5%) group of patients [1], there are still no adequate therapeutic strategies
Inhibits VEGFR1, 2, and 3, PDGFR-α and β, KIT, FMS-like tyrosine kinase 3 (FLT3), RET, and CSF1R [6]. It was studied on a preclinical neuroendocrine tumor model, thereby displaying a reduction in the glioma cells’ invasive capacity [6,7,8]
The results showed that compound 1 produced cell death of U87 MG tumor cells via apoptotic mechanism given the 4 h of contact at IC50 dose (Figure 5a)

Summary

Introduction

Even though glioblastoma is one of the most frequent and aggressive adult primary central nervous system tumors, with no more than two years of survival in a low percentage (3–5%) group of patients [1], there are still no adequate therapeutic strategies. As second-line chemotherapeutics, tyrosine kinase receptors (TKRs) inhibitors have been used [3,4,5], i.e., vascular endothelial growth factor (VEGF) receptor (VEGFR1 and 2) inhibitors. In this sense, the anti-tumor and anti-angiogenic agent sunitinib (Sun, Figure 1). Inhibits VEGFR1, 2, and 3, PDGFR-α and β, KIT, FLT3, RET, and CSF1R [6] It was studied on a preclinical neuroendocrine tumor model, thereby displaying a reduction in the glioma cells’ invasive capacity [6,7,8]. It has not been active in newly diagnosed glioblastoma patients [9] and in a single-arm phase II trial Sun displayed minimal anti-glioblastoma activity with high toxicity [10]

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