This work demonstrates that Erlotinib-decorated with 3D-boron-rich-cluster resulted in an anti-EGFR lead molecule with IC50 value of 2.3 nM, 10-fold higher than the parent Erlotinib.
The epidermal growth factor receptor (EGFR, ErbB1), is a transmembrane glycoprotein that consists of an extracellular binding domain, a single hydrophobic transmembrane segment, and an intracellular protein tyrosine kinase domain. Icosahedral carboranes have roughly the same molecular volume as adamantane (148 Å3 vs 136 Å3) but is more hydrophobic. As a consequence of their electronic structure, carboranes are aromatic and are therefore used as bioisosteres for phenyl groups.
Icosahedral boron clusters have emerged as interesting alternatives and promising scaffolds to be used in pharmaceutical drug design. However, these clusters have been an underexplored moiety in the development of EGFR kinase inhibitors.
In our previous studies we reported new anilinoquinazoline-icosahedral borane hybrids as glioma targeting for potential use in cancer therapy. The anti-glioma activity of the most powerful compound against glioma cells, a 1,7-closo-derivative, displayed at least 3.3 times higher activity than the parent drug erlotinib. According to the cytotoxic effects on normal glia cells, the hybrids were selective for epidermal growth factor receptor (EGFR)-overexpressed tumor cells. These boron carriers could be used to enrich glioma cancer cells with boron for cancer therapy.
In this article  we report that EGFR inhibitor incorporating closo-carborane has been shown to have higher affinity than Erlotinib. The comparative docking analysis with compounds bearing bioisoster-substructures, demonstrated the relevance of the 3D aromatic-boron-rich moiety for interacting into the EGFR ATP binding region. The capability to accumulate in glioma cells, the ability to cross the blood-brain barrier and the stability on simulated biological conditions render these molecules as lead compounds for further structural modifications to obtain dual action drugs to treat glioblastoma.
Marcos Couto,1,2,3 María Fernanda García,3 Catalina Alamón,1 Mauricio Cabrera,4 Pablo Cabral,3 Alicia Merlino,5 Francesc Teixidor,2 Hugo Cerecetto,1,3 and Clara Viñas2
1 Grupo de Química Medicinal, Lab. Química Orgánica, Fac. de Ciencias, Univ. de la República Iguá. Uruguay.
2 Institut de Ciència de Materials de Barcelona (ICMAB-CSIC), Spain
3 Área de Radiofarmacia, Centro de Investigaciones Nucleares, Fac. Ciencias, Univ. de la República, Uruguay.
4 Lab. I + D Moléculas Bioactivas, Centro Universitario Paysandú, CenUR Litoral Norte, Univ. de la República, Uruguay.
5 Lab. Química Teórica y Computacional, Instituto de Química Biológica, Fac. Ciencias, Univ. de la República, Uruguay.
Discovery of Potent EGFR Inhibitors through the Incorporation of a 3D-Aromatic-Boron-Rich-Cluster into the 4-Anilinoquinazoline Scaffold: Potential Drugs for Glioma Treatment.
Chemistry-A European Journal 24, 3122 – 3126 (2018)
The comparative docking analysis of EGFR inhibitor incorporating closo-carborane with compounds bearing bioisoster-substructures, demonstrated the relevance of the 3D aromatic-boron-rich moiety for interacting into the EGFR ATP binding region.