Plenary Lecture 11


Title: Looking for hybrid agents with potential use in BNCT of glioblastoma multiforme:
Tyrosine kinase inhibitors hybridized with boron clusters.

Professor Hugo Cerecetto

University of the Republic, Uruguay

Lecture Summary:
Boron neutron capture therapy (BNCT) is a radiation therapy for cancer that involves the irradiation of non-radioactive 10B-enriched tumors with low energy thermal neutrons to yield high linear energy transfer particles, 4He2+ and 7Li3+ ions. Due to the limited penetrable path length (5–9 mm, approximately the radius of a typical cell) of high-LET particles into tissues, the destructive effects of high-LET particles are localized within cells that contain boron atoms,1 which reduces damage to healthy tissues. Two B-derivatives are currently used in clinic for BNCT, BPA and BSH (Figure 1). The carborane cage (boron clusters) in BSH enriches cancer cells with B atoms because it possesses a large number of boron atoms per molecule. Chemically talking the boron clusters could be easily conjugated with organic molecules or target ligands.2

Figure 1

Glioblastoma multiforme (GM) is both the most common primary brain tumor and aggressive variant within the central nervous system. The standard treatment is surgical resection of the tumor followed by a combination of radiation and chemotherapy in order to kill any remaining tumor cells infiltrated the brain parenchyma. However, the current therapeutic success is limited.3 The targeted therapy is currently under investigation in the treatment of cancer, specifically inhibitors of tyrosine kinase domains. In this sense, tyrosine kinase inhibitors like erlotinib, lapatinib or sunitinib (Figure 2) have been described with some success for the treatment of GM.

Herein it will be described our search for hybrid agents tyrosine kinase inhibitors-boron clusters with potential use in BNCT for GM (see example in Figure 3). The design, synthesis, biological characterization and proof of concepts of tyrosine kinase domains inhibitors hybridized with boron cluster pharmacophores will be depicted.


Figure 2


Figure 3

Acknowledgments: We thank ANII (Uruguay), CSIC-Universidad de la República (Uruguay) and PEDECIBA (Uruguay) for financial supports.


References: 1 R. F. Barth, R. F.; Coderre, J. A.; Vicente, M. G. H.; Blue, T. E. Clin. Cancer Res. 2005, 11, 3987.

2 Leśnikowski, Z. J. J. Med. Chem. 2016, DOI: 10.1021/acs.jmedchem. 5b01932.

3 Adamson, C.; Kanu, O.; Mehta, A. I.; Di, C.; Lin, N.; Mattox, A. K.; Bigner, D. D. Expert Opin. Invest. Drugs. 2009,18,1061.